MXPA99000971A

MXPA99000971A - Potassium channel inhibitors

Info

Publication number: MXPA99000971A
Application number: MXPA/A/1999/000971A
Authority: MX
Inventors: Floyd Hughes Philip; Alexander Castle Neil; Patrick Hollinshead Sean; Serafin Mendoza Jose; Wendell Wilson Joseph; Amato George; Beaudoin Serge; Gross Michael; Mcnaughtonsmith Grant
Original assignee: Eli Lilly & Company; Icagen Inc
Priority date: 1996-07-26
Filing date: 1999-01-26
Publication date: 2000-02-02

Abstract

Compounds of general formula (I) wherein R 1 is H, alkyl or is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted carbocycloalkyl;R 2 is selected from the group consisting of alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted carbocycloalkyl;R 3 is hydrogen or methyl;R 4 is hydrogen or methyl;X 1 is C=O, C=S, or SO 2;X 2 is C=O or SO 2;Y 1 is O, (CH 2) p, CH 2O, HC=CH or NH;wherein p is 0, 1 or 2;Y 2 is O, (CH 2) q, HC=CH or NH;wherein q is 0 or 1;Z is H, OR 5 or NR 6R 7;wherein R 5 is H, (CH 2) m-R 8;or C(O)-(CH 2) m-R 8;m=1 to 5;R 8 is N(R 9) 2, N(R 9) 3L or CO 2R 9;wherein each R 9 is independently selected from H or alkyl;and L is a counter ion;R 6 is H or alkyl;R 7 is H, alkyl or CO 2R 10;wherein R 10 is alkyl;or pharmaceutically acceptable salts or prodrugs thereof are useful as potassium channel inhibitors and useful for the treatment of cardiac arrhythmias and cell proliferative disorders.

Description

INHIBITORS OF THE POTASSIUM CHANNEL BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention is broadly directed to a class of compounds useful as potassium channel inhibitors. 2. Description of Related Art Potassium channels, as a class of channels, are ubiquitously expressed in eukaryotic and prokaryotic cells, and are the key elements in the control of electrical and non-electrical cellular functions. Subclasses of these compounds have been termed based on the amino acid sequence and functional properties, and include, for example, voltage-fed potassium channels (e.g., Kv1, Kv2, Kv3, Kv4) and rectifier potassium channels towards inside (for example, Kir1, Kir2, Kir3, Kir4, Kir5, Kir6). The subtypes within these subclasses have been characterized by their putative function, pharmacology and distribution in cells and tissues (Chandy and Gutman, "Voltage-gated potassium channel genes" in Handbook of Receptors and Channels-Ligand and Voltage-gated Ion Channels, RA North, 1995, Doupnik et al., Curr Opin Neurobiol 5: 268, 1995). Inhibitors of potassium channels lead to a reduction in the movement of the potassium ion through the membranes of the cell. Consequently, such inhibitors induce the prolongation of the electrical action potential or the depolarization of membrane potential, in cells containing the inhibited or blocked potassium channels. The prolongation of the electrical action potential is a preferred mechanism for treating certain diseases, for example, cardiac arrhythmias (Colatsky et al., Circulation 82: 2235, 1990). Potential membrane depolarization is a preferred mechanism for the treatment of certain other diseases, such as those involving the immune system (Kaczorowski and Koo, Perspectives in Drug Discovery and Design, 2: 233, 1994). In particular, it has been shown that the blocking of potassium channels regulates a variety of biological processes including cardiac electrical activity (Lynch et al., FASEB J. 6; 2952, 1992; Sanguinetti, Hypertension 19: 228, 1992; Deal et al. ., Physiol. Rev. 76:49, 1996), neurotransmission (Halliwell, "K + channels in the central nervous system" in Potassium Channels, De. NS Cook, pp348, 1990), and T-cell activation (Chandy et al. , J. Exp. Med. 160: 369, 1984; Lin et al., J. Exp Med. 1977: 637, 1993). These effects are mediated through subclasses or specific subtypes of potassium channels. Several types of potassium channels have been cloned and expressed, which show the functional, pharmacological and tissue distribution characteristics, which make them potassium channel targets candidates for the treatment of diseases. For example, the delayed rectifier voltage-fed potassium channel called (lKur (Isus), which has been reported to contain the subunit gene product at Kv1.5, is generally thought to be important in the repolarization of the atrial action of a human being and thus is a candidate potassium channel target for the treatment of cardiac arrhythmias, especially those that occur in the atria (Wang et al., Circ Res.73: 1061, 1993; Fedida et al. ., Circ Res. 73: 210, 1993, Wang et al., J. Pharmacol, Exp. Ther 272: 184, 1995, Amos et al., J. Physiol., 491: 31, 1996). , lKn (which comprises the subunit gene product to Kv1.3) determines the resting membrane potential in human T lymphocytes (Leonard et al., Proc. Natl. Acad. Sci. 89: 10094, 1992; Kaczorowski and Koo , Perspectives in Drug Discovery and Design, 2: 233, 1994) and in this way is a candidate potassium channel target for the prevention of cell activation. ula T in the immune response under immunoreactive conditions (Lin et al., J. Exp Med. 177: 637, 1993). The present invention relates to compounds that are useful as inhibitors of the function of the potassium channel. The compounds of the invention are especially active as inhibitors of voltage-fed potassium channels. The potassium channel inhibitors of the invention, therefore, they can be used for the treatment of diseases in which the prolongation of cell action potentials could be beneficial, which include, but are not limited to, cardiac arrhythmias. In addition, the compounds of the invention can be used for the treatment of disorders where the induction of cell membrane depolarization, including, but not limited to, cell proliferative disorders, could be beneficial. It is an object of the present invention, therefore, to provide compounds that are useful for the treatment of diseases in mammals, including humans, and especially for the management of diseases treated by the inhibition of cell membrane potassium channels, such as the potassium channels responsible for the potassium current \ Kur cardiac, or the potassium channels responsible for the lKn potassium current of T lymphocyte, and potassium channels containing one of the Kv1.5 or Kv1 subunit gene product .3. Another object of the invention is to provide a method for treating diseases in mammals, including humans, that respond to the inhibition of the potassium channel function, such method comprises administering to a mammal in need thereof, a compound of the invention .

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 compares the effect of 3 nM margatoxin and 10 μM of 1 - (p-ethylphenyl) sulfimide-2-hydroxy-6- (m-methoxy) benzamido-indane, (compound 4), on the membrane potential in cells of Chinese hamster ovary (CHO) expressing human KV1.3 potassium channels (CHO-Kv1.3). The effect of 10 μM of compound 4 on the membrane potential in non-transfected CHO cells (CHO-WT) is also shown. Figure 2 compares the inhibitory effect of 10 μM of compound 4 on the increase in rubidium 86 (86Rb) emanation evoked by 60 mM KCl in CHO cells expressing human Kv1.3 or Kv1.5 potassium channels. Figure 3 illustrates the inhibition of potassium currents through compound 4 in CHO cells subject to voltage, expressing Kv1.3 or Kv1.5. Figure 4 shows action potentials produced in rat cardiac myocyte in the absence of drug (control), after a 2 minute application of 1 μM of compound 4, and after drug elimination. Figure 5 compares the inhibitory effect of 10 μM of the 4.1 nM compound of margatoxin (MgTx), and 50 nM of caribdotoxin (CTX) on the stimulation induced by phytohaemagglutinin (PHA) (1.25 or 2.5 μg / ml) of incorporation of 3H-thymidine in human T lymphocytes.

DETAILED DESCRIPTION OF THE INVENTION This invention describes compounds and their utility as inhibitors of voltage-dependent potassium channel function, particularly potassium channels (i.e., lKur.Kv1.5) which can serve as targets for the treatment of cardiac arrhythmias, especially those that occur in the atria (eg, atrial trepidation and atrial fibrillation (Wang et al., Cir. Res. 73: 1061, 1993; Fedida et al., Circ. Res. 73: 210, 1993; Wang et al., J. Pharmacol Exp. Ther. 272A8A, 1995), as well as the potassium channels (ie, lKn. Kv1.3) which can serve as targets for the treatment of immunological diseases (Kaczorowski and Koo, Perspectives in Drug Discovery and Design 2: 233, 1994.) Consequently, the present invention also provides a method for treating diseases that respond to the inhibition of potassium channel function, such as cardiac arrhythmias and various immunological diseases, using the compounds of the invention. invention is particularly based on the discovery that the compounds of the following formula (I) are inhibitors of the function of the potassium channel. In particular, these compounds have demonstrated activity against potassium channels / human currents l? -r. I? N > Kv1.5, Kv1.3. As a result, these compounds are useful in the treatment of cardiac arrhythmias and cell proliferative disorders. Thus, in a first aspect, the present invention relates to compounds having potassium channel inhibitory activity of the formula (I): wherein R1 is H, alkyl or is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; R2 is selected from the group consisting of an alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; R3 is hydrogen or methyl; R 4 is hydrogen or methyl; X1 is C = 0, C = S, or S02; X2 is C = 0 or S02; Y1 is O, (CH2) P, CH20, HC = CH or NH; wherein p is 0, 1 or 2; Y2 is O, (CH2) q, HC = CH or NH; where q is 0 or 1; Z is H, OR5 or NR6R7; wherein R5 is H, (CH2) m-R8; or C (0) - (CH2) m-R8; m = 1 to 5; R8 is N (R9) 2, N (R9) 3L or C02R9; wherein each R9 is independently selected from H or alkyl; and L is a counterion; R is H or alkyl; R7 is H, alkyl or C02R10; where R10 is alkyl. Suitable counterions, L, are described below and include as non-limiting examples bromide, chloride, acetate and tosylate. In another aspect, the present invention relates to indane compounds having potassium channel inhibition activity of the formula (II): wherein R 1 is H or an optionally substituted aryl selected from the group phenyl and β-naphthyl; R2 is selected from the group of an optionally substituted phenyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; m is 0 or 1; X is O or S; and Y is selected from one of (CH2) P, (CH20) q and (NH) r; wherein p is 0, 1 or 2; q is 0 or 1, and r is 0 or 1.

Preferably, R2 is phenyl per se or a phenyl substituted with one or more groups at the 2 (ortho), 3 (meta, or 4 (para) positions, wherein such groups are selected from alkyl of 1 to 6 carbon atoms, C 1 -C 6 alkoxy, cyano, halogen and trifluoromethyl Alternatively, R 2 is an optionally substituted heteroaryl, an optionally substituted heterocyclyl or an optionally substituted carbocycloalkyl, wherein such optionally substituted portions may be substituted with alkyl of 1 to 6 atoms of carbon, alkoxy of 1 to 6 carbon atoms, cyano, halogen and trifluoromethyl Very preferred are the compounds of the following formula (III): wherein R 1, R 2 and p again have the same meanings presented above, R 1 is preferably an aryl group selected from phenyl and β-naphthyl, and more preferably an aryl group substituted with groups such as alkyl of 1 to 6 carbon atoms, alkoxy from 1 to 6 carbon atoms, as well as cyano, trifluoromethyl and halogen. Similarly, R2 is an optionally substituted phenyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl or an optionally substituted carbocycloalkyl, each of which may be substituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms , cyano, halogen and trifluoromethyl. Examples of molecules, described under formulas (I) and (II) include: 11 12 13 14 17 18 21 22 23 24 26 Examples of compounds described under formula (III) include compounds 2, 4, 6, 8, 10, 11, 12, 13, 15, 16, 17, 19, 20, 24, 26, 27 and 28. An interesting subgroup of the compounds of Formula I is illustrated in Formula IV (shown below). wherein the variables are as described for Formula I with the stated preferences: R1 is preferably selected from the group of an optionally substituted aryl and an optionally substituted heteroaryl; R2 is preferably selected from the group of optionally substituted aryl and optionally substituted heteroaryl and Z preferably is H or OR5, R5 being as defined above. R and R2 are preferably portions that are not ionized at a physiological pH. The term "alkyl" used alone or in combination herein, refers to a straight or branched chain saturated hydrocarbon group containing from one to ten carbon atoms, and the terms, "alkyl of 1 to 6 carbon atoms" and "lower alkyl" refer to groups containing from one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl; tert-butyl and the like. The term "alkoxy" used alone or in combination herein, refers to a straight or branched chain alkyl group, covalently linked to the parent molecule through an -O- linkage containing from one to ten carbon atoms , and the terms "C 1-6 alkoxy" and "lower alkoxy" refer to groups containing from one to six carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and the like . The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group. The term "haloalkyl" is a substituted alkyl, preferably a substituted lower alkyl substituted with one or more halogen atoms, and is preferably an alkyl of 1 to 4 carbon atoms substituted with one to three halogen atoms. An example of a haloalkyl is trifluoromethyl. The term "alkanoyl" used alone or in combination herein, refers to an acyl radical, derived from an alkancarboxylic acid, particularly a lower alkancarboxylic acid and includes examples such as acetyl, propionyl, butyryl, valeryl and 4-methyl valeryl. The term "aminocarbonyl" means a carbonyl substituted with amino (carbamoyl or carboxamide) wherein the amino group can be a primary, secondary amino (monosubstituted amino) or tertiary amino (disubstituted amino), preferably having a lower alkyl substituent. The term "carbocycloalkyl" refers to stable, saturated or monocyclic partially unsaturated, monocyclic bridged, bicyclic and spiro-ring hydrocarbons of 3 to 15 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclohexyl, bicyclooctyl, bicyclononyl , espirononilo and espirodecilo. The term "optionally substituted" as referring to "carbocycloalkyl" herein, indicates that the carbocycloalkyl group may be substituted at one or more substitutable ring positions by one or more groups independently selected from alkyl (preferably lower alkyl), alkoxy ( preferably lower alkoxy), nitro, monoalkylamino (preferably a lower alkylamino), dialkylamino (preferably, a [lower] dialkylamino, cyano, halogen, haloalkyl, (preferably trifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkylamido (preferably lower alkylamido) , alkoxyalkyl (preferably, lower alkoxy-lower alkyl), alkoxycarbonyl (preferably a lower alkoxycarbonyl), alkylcarbonyloxy (preferably a lower alkylcarbonyloxy) and aryl (preferably phenyl), such aryl is optionally substituted by halogen, lower alkyl and lower alkoxy groups . The term "heterocyclyl" as used herein, refers to a stable, saturated or partially unsaturated, monocyclic, monocyclic, bicyclic, and spiro-ring system containing carbon atoms and other atoms selected from nitrogen, sulfur and / or or oxygen. Preferably, a heterocyclyl is a 5- or 6-membered monocyclic ring or an 8-11 membered bicyclic ring, which consists of carbon atoms and contains one, two or three heterogeneous atoms selected from nitrogen, oxygen and / or sulfur. The term "optionally substituted" as referring to "heterocyclyl" herein, indicates that the heterocyclyl group may be substituted at one or more substitutable ring positions by one or more groups independently selected from alkyl (preferably lower alkyl), alkoxy ( preferably lower alkoxy), nitro, monoalkylamino (preferably a lower alkylamino), dialkylamino (preferably, a dialkylamino [lower], cyano, halogen, haloalkyl, (preferably trifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkylamido (preferably lower alkylamido), alkoxyalkyl (preferably, lower alkoxy-lower alkyl), alkoxycarbonyl ( preferably a lower alkoxycarbonyl), alkylcarbonyloxy (preferably a lower alkylcarbonyloxy) and aryl (preferably phenyl), such aryl is optionally substituted by halogen, lower alkyl and lower alkoxy groups Examples of such heterocyclic groups are soxazolyl, imidazolinyl, thiazolinyl, imidazolidinyl, pyrrolyl, pyrrolinyl, pyranyl, pyrazinyl, piperidinyl, morpholinyl and triazolyl The heterocyclyl group can be attached to the structure of origin through a carbon atom or through any heterogeneous heterocyclyl atom resulting in a stable structure. heteroaryl "as used herein, refers to a monocyclic or bicyclic, aromatic, stable ring system containing carbon atoms and other atoms selected from nitrogen, sulfur and / or oxygen. Preferably, a heteroaryl is a 5- or 6-membered monocyclic ring (optionally benzofused) or an 8-11 membered bicyclic ring, which consists of carbon atoms and contains one, two or three heterogeneous atoms, selected from nitrogen, oxygen and / or sulfur. The term "optionally substituted" as referring to "heteroaryl" herein, indicates that the heteroaryl group may be substituted at one or more substitutable ring positions, by one or more groups independently selected from alkyl (preferably lower alkyl), alkoxy (preferably lower alkoxy, nitro, monoalkylamino (preferably lower alkylamino), dialkylamino (preferably, a [lower] dialkylamino, cyano, halogen, haloalkyl, (preferably trifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkylamido (preferably lower alkylamido) , alkoxyalkyl (preferably, lower alkoxy-lower alkyl), alkoxycarbonyl (preferably a lower alkoxycarbonyl), alkylcarbonyloxy (preferably a lower alkylcarbonyloxy) and aryl (preferably phenyl), such aryl is optionally substituted by halogen, lower alkyl and lower alkoxy groups Examples of tale Heteroaryl groups are isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridyl, furyl, pyrimidinyl, pyrazolyl, pyridazinyl, furazanyl and thienyl. The heteroaryl group can be attached to the structure of origin through a carbon atom or through any heterogeneous heteroaryl atom resulting in a stable structure. The specific chemical nature of the heterocyclyl and heteroaryl groups optionally substituted for the terminal portions R1 and R2 in the potassium channel inhibitor compounds identified above is not narrowly critical and, as noted above, contemplates a wide variety of substituent groups. Preferably, the substituents for the heterocyclyl and heteroaryl groups are selected such that the total number of carbon and heterogeneous atoms comprising the heterocyclyls and substituted heteroaryls is not greater than about 20. The terms "halo" and "halogen" as used in present, to identify substituent portions, represent fluorine, chlorine, bromine or iodine, preferably, chlorine or fluorine. The term "aryl" when used alone or in combination refers to a monocyclic or bicyclic aromatic hydrocarbon ring system, unsubstituted or optionally substituted. Preferred groups are phenyl or optionally substituted naphthyl. The aryl group may optionally be substituted at one or more substitutable ring positions by one or more groups independently selected from alkyl (preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro, monoalkylamino (preferably lower alkylamino), dialkylamino (preferably, a dialkylamino [lower], cyano, halogen, haloalkyl, (preferably trifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkylamido (preferably alkylamido) lower), alkoxyalkyl (preferably, lower alkoxy-lower alkyl), alkoxycarbonyl (preferably lower alkoxycarbonyl), alkylcarbonyloxy (preferably lower alkylcarbonyloxy) and aryl (preferably phenyl), such aryl is optionally substituted by halogen, lower alkyl and lower alkoxy groups. Preferably, the aryl group is phenyl optionally substituted with up to four and usually with one or two groups, preferably selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, as well as cyano, trifluoromethyl and halogen. The term "aralkyl" alone or in combination refers to an alkyl radical as defined above wherein a hydrogen atom is replaced with an aryl radical as defined above, and includes benzyl and 2-phenylethyl.

The term "alkoxycarbonyl" alone or in combination means a radical of the formula -C (0) -alcoxy, wherein alkoxy is as defined above. The term "alkylcarbonyloxy" alone or in combination represents a radical of the formula -0-C (0) -alkyl wherein alkyl is as defined above. The term "alkenyl" represents a straight or branched hydrocarbon, having two to seven carbon atoms, containing one or more double bonds, preferably one or two double bonds. Examples of alkenyl include ethenylene, propenylene, 1,3-butadienyl and 1, 3,5-hexatrienyl. Unless otherwise indicated, the term "optionally substituted" as used herein, refers to the substitution of a ring system at one or more positions with one or more groups selected from: alkyl of 1 to 6 atoms of carbon, alkoxy of 1 to 6 carbon atoms, an optionally substituted phenyl, cyano, halogen, trifluoromethyl, alkoxycarbonyl of 1 to 8 carbon atoms, alkylcarbonyloxy of 1 to 6 carbon atoms, mono- and bis- (alkyl of 1 to 6 carbon atoms) -carboxamide, alkylamido of 1 to 6 carbon atoms, nitro and mono and bis- (alkyl of 1 to 6 carbon atoms) -amino. The term "treating" as used herein, describes the management and care of a patient presenting a condition, disease or disorder for which the administration of a compound of the present invention alters the action or activity of a channel of potassium to prevent the onset of symptoms or complications associated with the condition, disease or disorders, to mitigate the symptoms or complications caused by the condition, disease or disorders, or to eliminate the condition, disease or disorder as a whole. The indane compounds of the above formulas useful as potassium channel inhibitors according to the present invention can be prepared according to the following sequential steps: (1) Nitriding 1-indanone to produce a nitroindanone, which is then separated from minor component byproducts; (2) Reduction of the product of step (1) to give the corresponding alcohol; (3) Submit the product of step (2) to an acid-catalyzed dehydration to give the corresponding indene; (4) Oxidation of the double bond of the product of step (3) to give the epoxide; (5) Reacting the epoxide of step (4) with ammonium hydroxide to give the aminoalcohol; (6) Protect the amino group of the aminoalcohol with a wide variety of the conventional protecting group A from amino protecting groups which are commonly employed to block or protect the -NH2 functionality, while reacting other functional groups in the parent compound. The species of the protecting group used are not critical since the derivatized -NH2 group is stable to the conditions of the subsequent reactions and can be removed at the appropriate point without interrupting the rest of the molecule. See, T.W. Greene and P. Wuts, Protective Groups in Organic Synthesis, Chapter 7 (1991). Preferred amino protecting groups are t-butoxycarbonyl (Boc), phthalimide, a cyclic alkyl and benzyloxycarbonyl; (7) Protect the hydroxyl group of the aminoalcohol with a conventional protecting group. A wide variety of hydroxy protecting groups is commonly used to block or protect the -OH functionality, while other functional groups of the parent compound react. The species of the protective group used are not critical since the derivatized group -OH is stable to the conditions of the subsequent reactions and can be removed at the appropriate point without interrupting the rest of the molecule. See T.W. Greene and P. Wuts, Protective Groups in Orqanic Synthesis, Chapter 7 (1991). A "hydroxy protecting group" includes one of the ether or ester derivatives of the hydroxy group commonly employed to block or protect the hydroxy group while performing different reactions to the functional groups in a compound. Hydroxy protecting groups include tert-butyldiphenylsilyloxy (TBDPS), tert-butyldimethylsilyloxy (TBDMS), triphenylmethyl (trityl), mono- or di-methoxytrityl, or an alkyl or aryl ester. (8) Deprotecting the amino-protected group of the product from step (7) resulting in an indane amino functional; (9) React the product of step (8) with a sulfonyl chloride to join a portion R'-S02-, where R 'is equivalent to R1 as defined in formula (I). The aminoalcohol is reacted in a suitable solvent with the sulfonyl chloride (R'S02CI) or sulfonyl anhydride in the presence of an acid scavenger. Suitable solvents in which the reaction can be conducted include methylene chloride and tetrahydrofuran. Suitable acid scavengers include triethylamine and pyridine; (10) Reduce the sulfonylated product of step (9) to give the corresponding aniline; Y (11) Acylate the product from step (10) to join the other substituent group, using RCOCI, where R is equivalent to R2 as defined in formula (I). (12) Deprotect the hydroxy-protected group from the acylated group to produce the desired compound.

It is recognized that there are at least two chiral centers in the compounds that fall within the scope of the present invention, and thus such compounds will exist as various stereoisomeric forms. Applicants intend to include all the various stereoisomers within the scope of the invention. Thus, this invention is intended to include the cis and trans isomers and the corresponding enantiomers of the compounds of the formulas I-IV. Although the compounds can be prepared as racemates and can suitably be used as such, individual enantiomers or preferably synthesized can also be isolated by known techniques, if desired. Such racemates and individual enantiomers and mixtures thereof are intended to be included within the scope of the present invention. The present invention also encompasses the pharmaceutically acceptable pro-drugs of the compounds of Formula I. A prodrug is a drug that has been chemically modified and may be biologically inactive at its site of action, but which is degraded or modified to a through one or more enzymatic processes or other processes in vivo to the bioactive form of origin. Generally, a pro-drug has a pharmacokinetic profile different from the original drug, so that, for example, it is more easily absorbed through the mucosal epithelium, and has a better salt formation or solubility and / or has a better systematic stability (for example, an increasing plasma half-life). Those skilled in the art will recognize that chemical modifications of an originating drug to produce a prodrug include: (1) terminal ester or amide derivatives, which are susceptible to being divided by esterases or lipases; (2) terminal peptides that can be recognized through specific or non-specific proteases; or (3) a derivative that causes the pro-drug to accumulate at a site of action through membrane selection, and combinations of the above techniques. Conventional procedures for the selection and preparation of pro-drug derivatives are described in H. Bundgaard, Design of Prodrugs, (1985). Those skilled in the art are well versed in the preparation of pro-drugs and are aware of their meaning. The compounds of the present invention can be used in their net form or in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. Examples of acids that can be employed to form pharmaceutically acceptable acid addition salts of the compounds of the present invention include inorganic acids, such as hydrochloric acid, sulfuric acid and phosphoric acid and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. These salts of this form include, but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate , 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylprionate, picarate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, groups containing basic nitrogen can be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides.; dialkylsulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides, and others. In this way, dispersible or water-soluble or oil-soluble products are generally obtained. The pharmaceutically acceptable salts of the compounds of the present invention may also exist as various solvates, such as water, methanol, ethanol, dimethylformamide, ethyl acetate, and the like. Mixtures of such solvates can be prepared. Such solvates are within the scope of the present invention. The pharmacological profile of the potassium channel inhibitory activity of the compounds of the present invention can be readily determined by those skilled in the art, using routine experimentation, such as the procedures and techniques illustrated in the examples that follow. Assays for determining the activity of the particular compounds can be employed in stably transfected cells to express a specific potassium channel, as well as natural mammalian cells. In particular, cells stably transfected to express a specific potassium channel, which have been treated with a voltage-dependent fluorescent dye, such as trimethinoxonol of bis- (1,3-dibutylbarbituric acid), can be used to measure the activity inhibitor of the potassium channel inhibitor compounds, possibly in comparison with known inhibitors. Alternatively, such cells can be primed with a detectable species such as 86Rb, and then attacked with a particular compound, under conditions otherwise suitable for activating the potassium channel, to determine the potassium inhibitory activity of the compound. The inhibitory activity of the potassium channel of a compound can also be determined using isolated mammalian cells and the entire celiac configuration of the known patch attachment technique (Hamill et al., Pflugers Archiv 39:85, 1981). These and other techniques can be readily employed by those skilled in the art to determine the level of activity of the potassium channel inhibitor compounds of the present invention. The compounds of the present invention can be administered through a variety of routes, including orally, parenterally, sublingually, intranasally, through an inhalation spray, rectally or topically, in dosage unit formulations containing carriers, auxiliaries and carriers. pharmaceutically acceptable, non-toxic, conventional, as desired. The term "parenteral" as used herein, includes subcutaneous, intravenous, intramuscular, intracardiac, or infusion techniques. Topical administration may also involve the use of transdermal administration such as transdermal patches or yonthoretic devices. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art, using suitable dispersing agents or humectants and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a parenterally acceptable, non-toxic diluent or solvent, for example, as a solution in 1,2-propanediol. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution, and an isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any soft fixed oil may be employed, including mono or diglyceride synthetics. In addition, fatty acids, such as oleic acid find use in the preparation of injectable products. Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols, which are solids at ordinary temperatures, but liquid at rectal temperature and, therefore, are they will melt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dose forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, substances other than inert diluents, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms can also comprise pH regulating agents. Tablets and pills can also be prepared with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise auxiliaries, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfume agents. The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed as mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The compositions herein in liposome form may contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art. See, for example, Prescott, De., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33, et seq. To select the preferred compounds of less preferred compounds, for example, the in vitro assays summarized under the subheading of BioEnsays are used below. Typically, a preferred compound will produce an average maximum blocking activity at a concentration ranging from about 10 nM to about 1 μM in the described in vitro assays. One skilled in the art will recognize that the final and optimal regimen dose will be determined empirically for any given drug. The total daily dose administered to a host in individual or divided doses may be an amount of, for example, 0.001 to 100 mg of active ingredient per kilogram of the body on a daily basis and more usually 0.01 to 10 mg / kg / day. The unit dose compositions may contain amounts such as submultiples thereof to form the daily dose. It is anticipated that a therapeutically effective serum concentration of active ingredient will be from 10 nM to 10 μM (5 ng / ml at 5 μg / ml). The amount of active ingredient that can be combined with the carrier materials to produce an individual dosage form will vary depending on the host treated and the particular mode of administration. However, it will be understood that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex and the patient's diet, the time of administration, the route of administration, the rate of excretion, if a drug combination is being used, and the severity of the particular disease. The present invention is explained in more detail in the following examples. These examples are intended to illustrate the invention, and should not be taken as limiting thereof. Unless otherwise indicated, all references to parts and percentages are based on weight and all temperatures are expressed in degrees Celsius. The scope of the invention is not constructed as merely consisting of the following examples.

EXAMPLES Preparation of the Compound Preparation 1 1. To a solution of 1-indanone (25 g, 0.189 mol) in H2SO4 (84 ml) at 0 ° C was added a solution of KNOs (8.33 g, 0.0824 mol) in H2SO4 (40 ml) in order to maintain an internal temperature below 15 ° C. After stirring at 0 ° C for 1 hour, the reaction mixture was poured into crushed ice and stirred vigorously for 30 minutes. The suspension was then filtered, dried with air and purified through LC (95% ethyl acetate / toluene), to give the indane nitrate (18.90 g, 56%) as a pale yellow solid. 2. A solution of the nitrated product (18.90 g, 0.107 mol) in methanol (300 ml) was cooled to 0 ° C and small portions of NaBH4 (4.04 g, 0.107 mol) were added in several portions. The reaction was then stirred overnight at 25 ° C. The solution was quenched at 0 ° C with methanolic HCl (200 ml), concentrated under reduced pressure, re-solvent in CH 2 Cl 2, washed with H 2 O, and the organic layer was reconcentrated to give the crude alcohol as a solid. coffee. 3. To a solution of the crude alcohol in toluene (300 ml), a catalytic amount of p-toluenesulfonic acid was added and the reaction was heated to reflux for 1 hour using a Dean Stark trap to remove the water. The organic layer was washed with saturated NaHCO 3 (3 x 200 ml), saturated aqueous, dried over MgSO 4, the solvent was removed under vacuum and the product was recrystallized from methanol to give the corresponding indene (13.41 g, 78% over two hours). steps) as a cinnamon-colored solid. 4. To a solution of indene (10.53 g, 0.0653 mol) in dichloromethane (350 ml) at 0 ° C was added m-CPBA (29 g, 0.0924 mol) in small amounts over the course of 1 hour. After stirring overnight at 25 C, the mixture was washed with saturated Na 2 SO 3 (2 x 200 mL), saturated aqueous, saturated aqueous NaHCO 3 (2 x 200 mL), filtered through a cotton plug and concentrated under vacuum. 5. A suspension of the resulting epoxide in concentrated NH 4 OH (250 ml) was heated overnight in an oil bath at 45 ° C. The next day, water was added and the basic aqueous layer was saturated with NaCl. The cloudy reaction mixture was extracted with THF until no more product could be seen through TLC. The organic layers were combined, dried over MgSO4, concentrated and recrystallized from ethyl acetate to give the corresponding amino alcohol (11.54 g, 91% over two steps), as a vivid cinnamon colored solid. 6. To a solution of the aminoalcohol (8.34 g, 0.0429 mol) in THF (200 ml) was added a solution of di-tert-butyldicarbonate (11.25 g, 0.0515 mol) in THF (50 ml). After stirring 1 hour at 25 ° C, the solvent was removed under reduced pressure and the resulting solid was recrystallized from ethyl acetate to provide the corresponding protected amino compound (11.34 g, 90%) as a white solid. 7. Under an N2 atmosphere, a 3-liter three-necked round bottom flask, equipped with an overhead stirrer and addition funnel, was charged with carboxylated polystyrene resin (70 g, 2.77 mmole, C02H / g resin), anhydrous dichloromethane (1000 ml), and anhydrous DMF (10 ml). Then, oxalyl chloride (60.75 ml, 0.582 mol) was added through a slow dropwise addition of an addition funnel. After heating to reflux overnight under N2. The solvent was removed under vacuum using a gas dispersion tube. The resin was subsequently washed with anhydrous dichloromethane (3 x 500 ml). Once the last wash was completed, the resin was dried under vacuum for 2-3 hours. At this time, the polymer was resuspended in dry THF (1000 ml) followed by the addition of dry pyridine (314 ml, 3.88 moles), DMAP (11.85 g, 0.0970 moles) and the protected amino compound (85.62 g, 0.291). moles). The mixture was refluxed for 10 days under an inert atmosphere. The solvent was removed by vacuum filtration and the resin was washed with THF (3 x 300 ml), CH 2 Cl 2 (3 x 300 ml), and dried overnight in a vacuum oven to provide a protected indane amino attached to the resin (122.18 g) as a tan resin. 8. In a round-bottomed flask equipped with a stir bar was placed the indane bound to the resin (28 mg, 0.02827 moles), 0.500 ml dichloromethane, and TFA (0.109 ml, 0.14135 nmol). The reaction mixture was stirred at 25 ° C overnight, the resin was collected through filtration, resuspended in 10% TEA / CH2Cl2, stirred for 15 minutes, filtered again, and finally washed with water. dichloromethane to provide the amino-protected species. 9. In a 10 ml round bottom flask was placed the unprotected amino-resin-bound species (0.02827 mmole) followed by 0.5 ml of a pyridine solution (0.03659 ml, 0.4524 mmole) and DMAP (0.518 mg, 0.004241 mmole) ) in dichloromethane. Then, a 1 M solution of an electrophile (e.g., a choline chloride) in dichloromethane (0.1838 ml, 0.1838 mmole) was added and the resulting mixture was stirred overnight at 25 ° C. At this time, the solvent was removed by vacuum filtration and the resin was washed with CH 2 Cl 2, DMF, methanol, DMF, methanol and CH 2 Cl 2. 10. To a solution of the corresponding acylated compound (0.02827 mmole) in DMF (0.625 ml) was added SnCl2 x 2 H20 (102 mg, 0.4524 mmole) to convert the nitro group to an amino group. After stirring at 25 ° C for 48 hours, the resin was isolated through filtration and washed with CH2Cl2, DMF, methanol, DMF, methanol and CH2, Cl2. 11. In a 10 ml round bottom flask, the amino functional compound (0.02827 mmol) was placed followed by 0.5 ml of a solution of pyridine (0.03659 mmoles) and DMAP (0.518 mg, 0.004241 mmoles) in dichloromethane. Then, a solution of 1 M of an electrophile (for example, sulfonyl chloride) in dichloromethane (0.1838 ml, 0.1838 mmole) was added and the resulting mixture was stirred overnight at 25 ° C. At this time, the solvent was removed by vacuum filtration and the resin was washed with 12. To a flask containing the compound from step 11 (0.02827 mmol), a 1 M solution of NaOH in methanol (0.375 mL, 0.375 mmol) and THF (0.400 mL) was added. After stirring overnight at 25 ° C, the reaction was neutralized with 4 M HCl in methanol (0.100 mL, 0.400 mmol), filtered resin and the filtrate was concentrated under reduced pressure to provide the desired target compound.

Preparation 2 trans-1-benzamido-2-acetoxy-6-aminoindane One part of trans-1-tert-butyloxycarbamido-2-hydroxy-6-nitroindane was dissolved in a mixture of pyridine (16 parts), 4-dimethylaminopyridine (0.15) parts) and THF as acetyl chloride (1.2 parts) was added dropwise. After several hours, the reaction was treated with cold water and the organic layer was separated. The organic solution was washed with 1N cold HCl, the organic layer was dried and the solvent was evaporated to give trans-1-tert-butyloxycarbamido-2-acetoxy-6-nitroindan. A solution of this amino and hydroxy protected nitroindane in THF was treated with a stream of dry HCl for 5 minutes, then stirred for an additional hour. The solution was carefully treated with cold saturated sodium bicarbonate, the organic phase was washed with water, dried and the solvent was evaporated to give trans-1-amino-2-acetoxy-6-nitroindan. A solution of the deprotected amino compound in a mixture of (16 parts) of pyridine, (0.15 parts) of 4-dimethylaminopyridine and CH 2 Cl 2 was treated with a solution of (1.2 parts) of benzoyl chloride and the reaction was stirred overnight. The reaction was emptied in ice-water. The organic layer was separated and consecutively washed with 1 N HCl and brine. The organics were dried and the solvent was evaporated to give trans-1-benzamido-2-acetoxy-6-nitroindan. A solution of this acylated product (one part) in DMF was treated with (16 parts of SnCl2.H20) and stirred overnight. The reaction was emptied in ice-water, the reaction was made basic and the mixture was extracted with CH2Cl2. The organic extracts were washed with brine, the solution was dried and the solvent was evaporated to give trans-1-benzamido-2-acetoxy-6-aminoindan.

Preparation 3 trans-1-benzamido-2-hydroxy-6-carboxamido-indane A solution of trans-1-benzamido-2-acetoxy-6-nitroindane (one part), prepared as described in Preparation 2, in EtOAc, it was treated with H2 (4.218 kg / cm2) in the presence of Pt02 for several hours. The catalyst was removed and the solvent was evaporated to give trans-1-benzamido-2-acetoxy-6-aminoindan. A solution of this aminoindane (1 part) in a mixture of pyridine (16 parts), 4-dimethylaminopyridine (0.15 parts) and CH2Cl2 was treated with a solution of choline chloride (RCOCI) (1.2 parts) and the reaction was stirred for the night. The reaction was emptied in ice-water, the organic layer was separated and consecutively washed with saturated aqueous sodium bicarbonate and brine. The organics were dried and the solvent was evaporated to give trans-1-benzamido-2-acetoxy-6-carboxamino-indane. A solution of this indane in 1 M NaOH in methanol was stirred overnight. The reaction was vacuum-ice-water and extracted with CH2Cl2. The extracts were washed with brine, dried and the solvent was evaporated to give the trans-1-benzamido-2-hydroxy-6-carboxamido-indane.

Preparation 4 trans-1-benzamido-2-hydroxy-6-carboxamido-indane A solution of (2 parts) of benzamide in DMF was treated with NaH (2 parts) and the reaction was stirred until the gas evolution ceased. A part of 1,2-epoxy-6-nitroindan was added to the reaction and the reaction was stirred overnight at 60 ° C. The reaction was emptied in ice-water and extracted with CH2Cl2- The organic extracts were washed with water, dried and the solvent was evaporated. The residue was chromatographed to give trans-1-benzamido-2-hydroxy-6-nitroindane. To a solution of nitroindane (1 part) in a mixture of pyridine (16 parts), (0.15 parts) of dimethylaminopyridine and an inert organic solvent such as THF or CH2Cl2, were added dropwise (1.2 parts) of acetyl chloride. After several hours, the reaction was treated with cold water and the organic layer was separated. The organic solution was washed with cold 1 N HCl, the organic layer was dried and the solvent was evaporated to give trans-1-benzamidoamido-2-acetoxy-6-nitro indan. Processing of this protected indane as in Preparation 2 provided the tarns-1-benzamido-2-hydroxy-6-carboxamido-indane.

Preparation 5 1-Benzamido-6-carboxamidoindane A mixture of 6-nitroindan-1 -one (1 part) and Raney-N i in EtOH was treated with hydrogen (4,218 kg / cm 2) for several hours. The catalyst was removed and the solvent was evaporated to give 6-aminoindan-1-one. A mixture of aminoindane (1 part) in a mixture of pyridine (16 parts), 4-dimethylaminoiridine (0.15 parts), and CH2Cl2 was treated with a solution of (1.2 parts) of acyl chloride and the reaction was stirred overnight . The reaction was emptied in ice-water, the organic layer was separated and consecutively washed with saturated aqueous sodium bicarbonate and brine. The organics were dried and the solvent was evaporated to give 6-carboxamido-indan-1 -one. A solution of this product (1 part) in a mixture of EtOH and NH 3 (5 parts) was treated with hydrogen (4,218 kg / cm 2) in the presence of Pd-C-sulforated. After several hours, the catalyst was removed and the solvent was evaporated to give 1-amino-6-carboxamido-indane. A solution of (1 part) of indane in a mixture of (16 parts) of pyridine, (0.15 parts) of dimethylaminopyridine, and CH2Cl2 was treated with a solution of (1.2 parts of benzoyl chloride and the reaction was stirred overnight The reaction was evacuated in ice-water, the organic layer was separated and consecutively washed with saturated aqueous sodium bicarbonate and brine The organics were dried and the solvent was evaporated to give the 1-benzamido-6-carboxamido-indane. The methods of column chromatography used standard flash chromatography techniques.A well-known reference describing suitable flash chromatography techniques is Still, WC Kahn, and Nitra, J. Org. Chem. 43: 2932 (1978). Fractions containing the product were generally evaporated under reduced vacuum to provide the product Optical rotations were obtained using methanol, pyridine, or other suitable solvent. and hydrochloride of the particular compound was prepared by placing the free base in diethyl ether. While this ether solution was stirred, a solution of HCl in diethyl ether was added dropwise until the solution became acidic. Alternatively, the ether solution was treated with dry HCl gas. The maleate salt of the particular compound was prepared by placing the free base in ethyl acetate and treating with maleic acid. The formed precipitate was filtered and dried to provide the corresponding maleate salt of the free base.

Preparation 6 Synthesis of Compound 4 To (100 ml) of ice-cold concentrated H2SO4 was added 1-indanone (15 g, 0.11 mol) followed by the slow addition (2 h) of KN03 (17 g, 1.5 eq) as a solution in concentrated H2SO4 (50 g). ml). The resulting mixture was poured on packed granulated ice (1.5 I) and diluted with water (the total aqueous layer was 1 L) and Et20 (1 L). The Et20 layer was separated and washed with water (2 x 200 ml). The combined aqueous layers were treated slowly with KOH (75 g) and extracted with CH 2 Cl 2 (2 x 500 ml). The combined CH2Cl2 layers were washed with water (500 ml). The combined organic layers were dried (Na2SO), filtered and treated with silica gel (30 g). The resulting solid was applied to a column of silica gel (2.5"x 13") and purified by flash chromatography. Removal of the solvent provided the product as a solid (14.5 g, 74%). Rf (silica gel): 0.23 (30% EtOAc, 70% hexanes), 1 H NMR (300 MHZ, CDCl 3) d 8.42 (s, 1 H), 8.37 (dd, J = 2.1, 8.4, 1 H), 7.65 (d , J = 8.3, 1H), 3.26 (m, 2H), 2.78 (m, 2H), 13C NMR (75MHZ, CDCl3) d 204.71, 160.94, 147.76, 138.04, 128.73, 127.88, 118.90, 36.49, 25.98.

The 6-nitro-1-indanone (14.5 g, 0.082 mmol) was dissolved in MeOH (160 ml) and cooled to 0 ° C. NaBH4 (32 g, 1. eq, granular) was added in 5 portions with an interval of 20 minutes. The resulting mixture was allowed to stir for 12 hours, slowly until reaching room temperature. The mixture was then cooled to 0 ° C again, treated dropwise with 6N HCl (40 ml, 3 eq) and diluted with water (800 ml) and (400 ml) of CH2Cl2. The aqueous layer was separated and extracted with CH2Cl2 (2 x 100 mL). The combined organic layers were dried (Na2SO4) and filtered. Removal of the solvent provided the product as a solid (14.6 g, 99%) which was used in the next step without further purification. Rf (silica gel): 0.15 (5% EtOAc, 45% hexanes, 50% CH2Cl2).

The 1-hydroxy-6-nitroindane (14.6 g, 0.082 mol) was heated with p-TsOHH20 (1.5 g, 0.1 eq) in PhMe (80 ml) for 3 hours at 90 ° C. The majority of the solvent was removed and the resulting mixture was diluted with CH2Cl2 (240 mL). The m-CPBA (34 g, 1.2 eq) was added in four portions at 20 minute intervals. The mixture was allowed to stir for 12 hours, treated with (400 ml) of saturated aqueous NaHCO 3, stirred for 30 minutes, and then diluted with (200 ml) of water and (100 ml) of CH 2 Cl 2. The aqueous layer was separated and extracted with CH2Cl2 (2 x 100 mL). The combined organic layers were dried (Na 2 SO 4) and filtered (2"silica gel). Removal of the solvent gave the product as a solid (14 g, 96%) which was used in the next step without further purification. Rf (silica gel): 0.49 (5% EtOAc, 45% hexanes, 50% CH2Cl2) .1H NMR (300 MHZ, CDCl3) d 8.34 (s, 1H), 8.16 (d, J = 8.2, 1H), 7.38 (d, J = 8.2, 1H), 4.35 (d, J = 1.9, 1H), 4.22 (d, J = 2.7 1H), 3.31 (d, J = 18.9, 1H), 3.06 (dd, J = 2.5 , 18.8, 1H).

The 6-nitro-1,2-epoxyindane (3.0 g, 17 mmol) was suspended in concentrated NH OH (60 ml) and stirred for 12 hours at 35 ° C and for 4 hours at 50 ° C. The resulting dark mixture was diluted with (170 ml) brine, saturated with NaCl, subjected to a moderate vacuum, and stirred with 15% l-PrOH / CHCl3 (170 ml). The aqueous layer was separated and extracted with 15% l-PrOH / CHCl3 (4 x 50 ml). The combined organic layers were dried (Na2SO4) and filtered. Removal of the solvent provided the product as a tan solid (3.0 g, 91%) which was used in the next step without further purification. R (silica gel): 0.20 (2% AcOH, 18% MeOH, 80% CHCl3).

To an ice cooled suspension of the aminoindane derivative (390 mg, 2.0 mmol) (6 ml) of dry CH 2 Cl 2 was added NEt 3 (0.33 ml, 1.2 eq), followed by the slow addition of sulfonyl chloride (451 mg, 1.1 eq) as a solution in (2 ml) of CH2Cl2. The ice bath was stirred and the heterogeneous mixture was allowed to stir for 3 hours. The resulting homogeneous mixture was diluted with (8 mL) of CH2Cl2, (8 mL) of water and (2 mL) of saturated aqueous NH4CI. The organic layer, together with the precipitated product, was separated from the aqueous layer. The aqueous layer was extracted with CH2Cl2 (3 x 2 ml). The combined organic layers were treated with l-PrOH (3 mL), dried (Na2SO), and filtered. The majority of the solvent was removed and hexanes / CH2Cl2 (1/1, 20 ml) was added to the resulting solid. The solid was filtered, washed with hexanes / CH 2 Cl 2 (1/1, 10 ml) and subjected to high vacuum to provide the product. (600 mg, 83%). Rf (silica gel): 0.27 (30% EtOAc, 20% hexanes, 50% CH2Cl2). 1 H NMR (300 MHz, CDCl 3) d 7.97 (d, J = 8.3, 1 H), 7.81 (d, J = 8.2, 2 H), 7.33 (d, J = 7.9, 2 H), 7.21-7.26 (m, 2 H) , 4.49 (d, J = 6.1, 1H), 4.36 (dd, J = 7.2, 13.8 1H), 3.30 (bs, 2H), 3.21 (dd, J = 7.1, 16.7, 1H), 2.78 (dd, J = 7.4, 16.8, 1H), 2.69 (q, J = 7.7, 2H), 1.21 (t, J = 7.5, 3H). 13C NMR (75MHZ, CDCI3) d 150.35, 147.44, 147.35, 141.41, 137.57, 128.84, 126.96, 125.60, 123.87, 119.57, 79.33, 64.55, 37.66, 28.53, 14.62.

To a suspension of the nitroindane derivative (52 g, 14 mmol) in (70 ml) of absolute EtOH was added SnCl22H20 (13 g, 14 eq). After heating the mixture at 50 ° C for 12 hours, the majority of EtOH was removed and the resulting residue was treated with (70 ml) of CHCl 3 (140 ml) of saturated aqueous NaHCO 3 and (70 ml) of water. The mixture was stirred for 30 minutes and then diluted with 15% l-PrOH / CHCl3 (70 ml) and water (70 ml). The aqueous layer (containing a precipitated tin by-product) was extracted with 15% l-PrOH / CHCl3 (3 x 70 ml). The combined organic layers were dried (Na2SO) and filtered. Removal of the solvent provided the product as a solid (4.5 g, 97%), which was used in the next step without further purification. Rf (silica gel): 0.23 (30% EtOAc, 20% hexanes, 50%, CH2Cl2).

Compound 4 To an ice-cooled suspension of the 6-aminoindane derivative (2.3 g, 6.9 mmoles) in dry CH2Cl2 (21 ml) was added acid chloride (1.2 g, 1.05 eq) followed by the slow addition of NEt3 (1.2 ml, 1.2 eq). The ice bath was removed and after 1 hour, the resulting homogeneous mixture was treated with (20 ml) of CH2Cl2, (35 ml) of water and (7 ml) of saturated aqueous NH CI. The aqueous layer was separated and extracted with CH2Cl2 (3 x 20 ml). The combined CH2Cl2 layers were dried (Na2SO), filtered and treated with silica gel (7 g). Evaporation of the solvent provided a solid which was applied to a column of silica gel (1.5"x 9") and purified by flash chromatography. Removal of the solvent gave the product as a crystalline solid (3.0 g, 93%). Rf (silica gel): 0.16 (30% EtOAc, 20% hexanes, 50% CH2Cl2). 1 H NMR (300 MHz, DMSO-d 6) d 10.16 (s, 1 H), 8.09 (d, J = 8.3, 1 H), 7.80 (d, J = 8.4, 2 H), 7.37-7.59 (m, 7 H), 7.10 -7.15 (m, 2H), 5.03 (d, J = 5.6, 1H), 4.40-4.45 (m, 1H), 4.03-4.09 (m, 1H), 3.83 (s, 3H), 3.02 (dd, J = 6.8, 15.8, 1H), 2.64 (q, J = 7.5, H), 2.50-2.57 (m, 1H), 1.16 (t, J 0 7.7 3H), HRMS (FAB) m / e calculated for C25H2 N205S (MH +) 467.1640, obsd. 467.1648. The separation of the enantiomers of compound 4 was carried out by HPLC with a column of Chiralpak AS (Chiral Technologies), eluting with hexanes / ethanol / methanol (60/20/20). The analytical separation of the enantiomers with a 4.6 mm x 250 mm column and a flow velocity of 1 μl / minute resulted in retention times of 6.7 (1R, 2R), and 11.1 (1S, 2S) minutes. Alternatively, compound 4 can be prepared enantioselectively through the asymmetric epoxidation shown below.

To a solution of 5-nitroindene (1.28 g, 7.94 mmol in CH 2 Cl 2 (5 ml) was added 4.15 mg (2.42 mmol of 4-phenylpyridine N-oxide followed by 154 mg (0.24 mmol) of (S, S) chloride. ) -N, N'-bis- (3,4-di-tert-butylsalicidene) -1,2-cyclohexanediamine-manganese (lll) After cooling to 0 ° C, 12 ml of 0.05 M NaH2P04 was added, followed 10-13% ice-cold NaOCI After 1 hour at 0 ° C, the reaction mixture was filtered (celite) and washed with CH 2 Cl 2 (200 ml) .The aqueous layer was separated and extracted with CH 2 Cl 2 (50 mL). ml) The combined organic phase was washed with (50 ml) of water and (50 ml) of brine, and then dried over Na 2 SO 4 Purification through flash chromatography using silica gel (1: 1 hexanes: Et20) gave (1S, 2R) -eperoxide (988 mg, 71%, 70% ee) as a yellow solid.The enantiomer excess was determined by HPLC with a Chiralcel OB-H column (Chiral Technologies), eluting with hexanes / isopropyl alcohol ico (80/20, 1 ml / minute) With a 4.6 mm 250 mm column, the retention times of the enantiomers are 33.6 and 36.3 minutes. This epoxide enriched with enantiomers was then used to prepare enantioenrichment compound 4 as described above. The additional enantioenrichment (> 90% ee) was obtained through recrystallization of compound 4 from l-PrOH-hexanes.

Preparation 7 Synthesis of Compound 24 Compound 24 To a heterogeneous mixture of the carboxylic acid (36 mg, 1.1 eq) and CH2Cl2 (2.5 ml) was added HOBt (39 mg, 1.2 eq), followed by EDC (60 mg 1.3 eq). After 20 minutes, a homogeneous mixture was presented, which was treated with the 6-aminoindane derivative (80 mg, 0.24 mmol). After stirring for 6 hours, the mixture was diluted with (2 ml) of CHCl3 (2 ml) of brine and (2 ml) of saturated aqueous NaHCO3. The aqueous layer was separated and extracted with CHCl3 (3 x 2 ml). The combined organic layers were dried (Na2SO4), filtered and treated with (300 mg) of silica gel. Removal of the solvent provided a solid which was applied to a column of silica gel (0.5"x 7") and purified by flash chromatography. Removal of the solvent proportions the product as a solid (108 mg, 100%). Rf (silica gel): .45 (50% EtOAc, 50% CH2Cl2). 1 H NMR (300 MHz, CDCl 3) d 9.95 (s, 1 H), 7.98 (d, J = 7.8, 1 H), 7.87 (d, J = 8.2, 2 H), 7.73 (dd, J = 7.6, 7.6, 1 H) , 7.37 (d, J = 8.1, 1H), 7.20-7.35 (m, 4H), 7.08 (d, J = 8.1, 1H), 6.93 (d, J = 5.6, 1H), 4.30-4.50 (m, 2H ), 3.13 (dd, J = 6.7, 15.4, 1H), 2.50-2.80 (m, 6H), 1.14 (t, J = 7.6, 3H). 3C NMR (75 MHz, CDCI3) d 162.53, 157.36, 149.69, 148.57, 139.70, 137.84, 137.28, 136.29, 135.68, 128.62, 127.32, 126.42, 125.38, 120.86, 119.47, 116.14, 80.41, 65.17, 37.06, 28.50, 23.94 , 14.72.

Preparation 8 Synthesis of Compound 22 Compound 22 A suspension of the 6-amidoindane derivative (0.174 g, 0.373 mmol) in dry CH2Cl2 (10 mL) was treated with EDC-HCI (0.120 g, 0.626 mmol), 4-DMAPO (0.100 g, 0.819 mmol), NEt3 (0.080 mL) , 0.57 mmole) and mono-methyl succinate (0.079 g, 0.60 mmole). The resulting homogeneous reaction mixture was stirred at room temperature for 2.5 hours and treated with (15 ml) of water, (15 ml) of saturated aqueous NH 4 Cl and (20 ml) of CH 2 Cl 2. The organic layer was separated, washed with brine, dried (Na 2 SO), filtered and concentrated. Flash chromatography on silica gel provided the product as a soft solid (0.190 g, 88%). Rf (silica gel): 0.75 (20% hexanes: 20% CH2CI2: 60% EtOAc). 1 H NMR (300 MHz, DMSO-d 6 d 9.59 (s, 1 H), 7.88 (d, J = 8.4 Hz, 2 H), 7.68-7.56 (m, 3 H), 7.47 (d, J = 8.4 Hz, 2 H), 7.42-7.39 (m, 1H), 7.19-7.11 (m, 3H), 5.17 (q, J = 6.9 Hz, 1H), 4.90 (m, 1H), 3.88 (s, 3H), 3.63 (s, 3H) , 3.29 (dd, J = 8.7 and 15.9 Hz, 1H), 2.81-2.26 (m, 8H), 1.25 (t, J = 7.8 hz, 3H); HRMS (FAB) m / e calculated for C3oH33N208S (MH +) 581.1958; obsd 581-1958.

Preparation 9 Synthesis of Compound 25 To a solution of 6-nitro-1-indanone (2.0 g, 12 mmol) in MeOH (25 mL) was added NH4OAc (9.4 g, 10 eq) followed by NaCNBH3 (830 mg, 1.1 eq). The mixture was stirred at 45 ° C for 40 hours and then filtered (celite). The solvent was removed and the resulting residue was added (60 ml) of water and (60 ml) of Et20. The aqueous layer was separated, treated with (24 ml) of 6 N NaOH, saturated with NaCl, and extracted with CHCl3 (1 x 60 ml then 3 x ml). The combined CHCl3 layers were dried (Na2SO), filtered and treated with 4N HCl / dioxane (2 mL, 0.6 eq). Removal of the solvent provided a solid, which was stirred with Et20 dry (120 ml, 1 hour) and filtered. The HCl salt of the product was thus obtained as a solid (900 mg, 35%) was used in the next step without further purification. Rf (silica gel): 0.13 (1% AcOH, 9% MeOH, 90% CHCI3). 1 H NMR (300 MHz, CD 3 OD) d 8.47 (d, J = 1.7, 1 H), 8.25 (dd, J = 2.1, 8.4, 1 H), 7.59 (d, J = 8.4, 1 H), 4.90-5.10 (m, 1H, solvent interference), 3.20-3.35 (m, 1H), 3.05-3.20 (m, 1H), 2.65-2.80 (m, 1H), 2.15-2.30 (m, 1H). 13 NMR (75 MHZ, CD3OD) d 152.10, 147.60, 140.26, 125.96, 124.55, 119.78, 54.71, 30.23, 29.73.

To a suspension of the hydrochloride salt of 1-amino-6-nitroindane (900 mg, 4.2 mmol) in dry (8 ml) CH 2 Cl 2 was added NEt 3 (1.4 ml, 2.4 eq). The resulting homogeneous mixture was then treated with sulfonyl chloride (940 mg, 1.1 eq) and stirred for 3 hours. The resulting heterogeneous mixture was diluted with (8 mL) of CH2Cl2 (8 mL) of water and (4 mL) of saturated aqueous NH4CI. The aqueous layer was separated and extracted with CH2Cl2 (3 x 4 mL). The combined organic layers were dried, (Na 2 SO) filtered and treated with 4 g of silica gel. Removal of the solvent provided a solid, which was applied to a column of silica gel (1.5"x 9.5") and purified by flash evaporation chromatography. Removal of the solvent provided the product as a solid (1.28 g, 88%). Rf (silica gel): 0.29 (30% EtOAc, 70% hexanes). 1 H NMR (300 MHZ, CDCl 3) d 7.98 (dd, J = 1.9, 8.2, 1 H), 7.70-7.85 (m, 3 H), 7.25-7.40 (m, 3 H), 5.77 (d, J = 9.2, 1 H) , 4.82 (dd, = 7.9, 16.3, 1H), 2.85-3.00 (m, 1H), 2.65-2.85 (m, 3H), 2.25-2.40 (m, 1 H), 1.75-1.90 (m, 1H), 1.26 (t, J = 7.6, 1H). 13 C NMR (75 MHz, CDCl 3) d 150.45, 149.64, 147.39, 144.16, 137.88, 128.82, 127.04, 125.32, 123.66, 119.62, 57.85, 34.36, 29.92, 28.60, 14.78.

The 6-nitroindane derivative (1.09g, 3.15 mmoles) and SnCl2H20 (3.6 g, 5 eq) were treated at 50 ° C in 3 mL of absolute EtOH for 12 hours. The majority of the EtOH was removed and the resulting residue was diluted with 30 ml of CH 2 Cl 2, 30 ml of water and 30 ml of saturated aqueous NaHCO 3. After stirring for 30 minutes. The aqueous layer was separated and extracted with CH2Cl2 (3 X 30 mL). The combined organic layers were dried with (Na2SO4), filtered and treated with 2 g of silica gel. Removal of the solvent provided a solid, which was applied to a column of silica gel (1.0"x 11") and purified by flash chromatography. Removal of the solvent provided the product as a solid (906 mg, 91%). Rf (silica gel): 0.16 (15% EtOAc, 35% Hexanes, 50% CH2Cl2). 1 H NMR (300 MHz, CDCl 3) d 7.84 (2H), 7.35 (21-1), 6.93 (1H), 6.53 (1H), 6.39 (1H), 5.20 (1H), 4.70 (1H), 3.51 (2H), , 2.50-2.85 (4H), 2.24 (11-1), 1.66 (1H), 1.28 (3H). 13C NRM (75 MHZ, CDCI3) d 149.52, 145.46, 143.37, 138.52, 132.53, 128.60, 127.24, 125.20, 115.55, 110.73, 58.57, 34.72, 28.92, 28.62, 15.01. HRMS (FAB) m / e cale. For C17H20N2O2S (M) 316.1245, obs. 316.1245.

To a solution of the 6-aminoindane derivative (200 mg, 0.63 mmol) in 3 ml of dry CH 2 Cl 2, acid chloride (120 mg, 1.1 eq) was added followed by NEt 3 (0.11 ml, 1.2 eq). The mixture was allowed to stir O / N and then diluted with 6 ml of water, 1 ml of saturated aqueous NH 4 Cl and 100 ml of CHCl 3. The CHCI3 layer was separated, dried (Na2SO) and filtered. Solvent removal provided a solid which was washed with Et20. In this way, the product was obtained as a white solid (260 mg, 92%) Rf (silica gel): 0.28 (15% EtOAc, 25% Hexanes, 50% CH2Cl2). 1 H NMR (300 MHz, DMSO-c.6) d 10.18 (s, 1 H), 8.07 (d, J = 9.1, 1 H), 7.78 (d, = 8.1, 2 H), 7.69 (S, 1 H), 7.62 ( d, = 8.1), 7.35-7.55 (m, 5H), 7.10-7.20 (m, 2H), 4.60-4.75 (m, 1H), 3.83 (s, 3H), 2.50-2.80 (m, 4H), 1.80 -1.95 (m, 1 H), 1.45- 1.60 (m, 1H), 1.18 (t, = 7.6.3H). HRMS (FAB) m / e caled. For C25H27N204S (MH +) 451.1691, obsd. 451.1692.

Preparation 10 Synthesis of the Cis Analog of Compound 4 Trifluoromethanesulfonic acid (0.73 ml, 8.3 mmol) was added dropwise to a slurry of 5-nitroindene oxide (735 mg, 4.15 mmol) in CH3CN (6.8 ml) at -40 ° C. After 20 minutes, the reaction mixture was allowed to warm to room temperature for one hour and then 4 ml of water was added.

After stirring for 10 minutes, the acetonitrile was removed by atmospheric distillation (vessel temperature 100 ° C).

The aqueous residue was maintained at 100 ° C for a further 5 hours and then cooled to room temperature. The aqueous phase was extracted with CH2Cl2 (10 ml) then basified with 1N NaOH to a pH of 13 and extracted with CH2Cl2 (3x10 ml). The organics were combined, dried (Na2SO) and concentrated under reduced pressure. Instant evaporation chromatography (5% MeOH / 95% EtOAc) of the residue provided the cis amino alcohol as a brown solid (518 mg, 64%). 1 H NMR (300 MHz, CDCl 3) d 8.17 (s, 1 H), 8.13 (d, = 7.1 Hz, 1 H), 7.38 (d, J = 8.1 Hz, 1 H), 4.50-4.45 (m, 1 H), 4.45 -4.40 (m, 1H), 3.52-3.49 (m, 1H), 3.17-3.03 (m, 1H), 1.43 (s, 9H). This product was converted to the cis analog of compound 4 using the procedures described in the synthesis of compound 4.

Preparation 1 Synthesis of Compound 21 A solution of 5-nitroindene (800 mg, 4.97 mmol) and urea-butyl N, N-dichloro-carbamate (924 mg, 4.97 mmol) in toluene (10 mL) was heated at 50 ° C for 5 hours. The resulting solution was cooled to 0 ° C and stirred with a 10 ml solution of sodium metabisulfite for 20 minutes. The organics were extracted with ether (2 x 10 ml), dried (Na 2 SO 4), and concentrated under reduced pressure. Flash chromatography (80% hexanes / 20% Et 2 O) provided the desired product as a colorless oil (312 mg, 22%). 1 H NMR (300 MHz, CDCl 3) d 8.27 (s, 1 H), 8.17 (dd, = 8.3, 2.0 Hz, 1 H), 7.40 (d, J = 8.4 Hz, 1 H), 5.28 (bs, 1 H), 4.84 ( bs, 1H), 4.45 (m, 1H), 3.52 (dd, J = 17.0.7.3 Hz, 1H), 3.04-2.98 (m, 1 H), 1.46 (s, 9H).

Sodium azide (222 mg, 3.43 mmol) was added to a stirring solution of the nitroindane derivative (715 mg, 2.28 mmol) in DMSO (3 mL) at room temperature. The resulting purple solution was heated at 50 ° C for 14 hours, cooled to room temperature and diluted with 5 ml of water. The organics were extracted with EtOAc (4 x 5ml), dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (80% hexanes / 20% Et2O) of the residue provided the desired product as a colorless oil (675 mg, 68%). 1 H NMR (300 MHz, CDCl 3) d 8.17 (s, 1 H), 8.13 (m, 1 H), 7.38 (d, J = 8.1 Hz, 1 H), 5.74 (bs, 1 H), 4.93 (d, = 5.9 HZ, 1H), 4.61-4.50 (m, 1H), 3.20 (dd, = 1β.6.7.4 Hz, 1H), 2.92 (dd, J = 16.6.9.0HZ, 1H), 1.43 (s, 9H).

BocHN "" Triphenylphosphine (270 mg, 1.03 mmol) was added to a stirring solution of the azidonitroindane derivative (300 mg, 0. 94 mmol) in THF (4 ml) at room temperature. After 1 hour, the solvent was removed under reduced pressure and replaced with 4 ml of MeOH. The new solution was cooled to 0 ° C and sodium borohydride (36 mg, 0.94 mmol) was added in portions. After 30 minutes at 0 ° C, 5 drops of glacial acetic acid were added. The reaction was concentrated to dryness and taken up in 20 ml of EtOAc. The organic phase was washed with 1N HCl (2 x 10 ml) and the aqueous phase was basified to a pH of 11 with 1N NaOH and re-extracted with EtOAc (3 x 10 ml). The organics were combined, dried (Na2SO4), and concentrated under reduced pressure to provide the desired product as a pale brown solid (196 mg, 71%). 1 H NMR (300 MHz, CDCl 3) d 8.17 (s, 1 H), 8.06 (dd, = 8.2, 1.9 Hz, 1 H), 7.32 (d, J = 8.3 Hz, 1 H), 5.27 (bs, 1 H), 4.41 ( bs, 2H), 3.28-3.21 (m, 1H), 2.94-2.87 (m, 1H), 1.42 (s, 9H).

P-Ethylsulfonyl chloride (240 mg, 1.17 mmol) was added to a stirring solution of the aminonitroindane derivative (330 mg, 1.12 mmol) and triethylamine (171 μL, 1.23 mmol) in THF (5 ml) at 0 ° C. The reaction was then heated at 50 ° C for 2 hours, cooled and 15 ml of EtOAc were added. The organics were washed with 10 ml of brine, dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (50% hexanes / 50% Et2O) of the residue provided the desired product as a white solid (247 mg, 48%). 1 H NMR (300 MHz, CDCl 3) d 8.07 (d, J = 8.4, 2.1 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 2 H), 7.39-7.31 (m, 4 H), 5.20-4.98 (m, 2H), 4.81-4.73 (m, 1H), 4.44 (p, J = 6.7 Hz, 1H), 3.25 (dd, J = 16.7.6.5 Hz, 1H), 2.89 (dd, J = 17.2, 6.4 Hz, 1H ), 2.72 (q, J = 7.5 Hz, 2H), 1.45 (s, 9H), 1.29 (t, J = 7.6 Hz, 3H).

Sodium borohydride (68 mg, 1.7 mmol) was added in portions to a stirring suspension of the nitroindane derivative (168 mg, 0.36 mmol) and nickel chloride (10 mg, 0.08 mmol) in THF / methanol 81: 1, 3 ml) at 0 ° C. After 20 minutes, the reaction mixture was quenched with 5 mL of water, extracted with EtOAc (3 x 10 mL), dried (Na2SO4), and concentrated under reduced pressure to provide the desired product as a pale brown solid. (156 mg, 99%) 1 H NMR (300 MHZ, CDCl 3) d 7.81 (d, J = 8.3 Hz, 1 H), 7.36 (d, = 8.1 Hz, 1H), 6.92 (d, = 7.9 Hz, 1H), 6.53 (d, = 7.0 Hz, 1H), 6. 11 (bs, 1H), 5.04-4.92 (bs, 2H) 4.63-4.55 (bs, 1H), 4.32-4.24 (m, 1H), 3.04-2.94 (m, 1H), 2.75 (q, = 7.5 Hz, 2H), 2.68-2.55 (m, 1H), 1.43 (s, 9H), 1.25 (t, J = 7.5 HZ, 3H) .

M-Anisoyl chloride (6.5 μL, 0.046 mmol) was added to a stirring solution of the aminoindane derivative (20 mg, 0.046 mmol) and triethylamine (7.7 μL, 0.055 mmol) in THF (3 mL) at 0 ° C. After 30 minutes, the reaction mixture was diluted with EtOAc (10 mL), washed with 10 mL of brine, dried (Na2SO4) and extracted under reduced pressure, flash chromatography (50% hexanes / 50%). EtOAc) of the residue provided the desired product as a white solid (22 mg, 84%). 1 H NMR (300 MHz, CDCl 3) d 7.84 (d, = 8.4 Hz, 1 H), 7.70-7.61 (m, 2 H), 7.40-7.34 (m, 4 H) 7.18 (d, J = 8.1 Hz, 1 H), 7.11 -6.91 (m, 2H), 4.98 (d, J = 8.0 Hz, 1H), 4.98-4.90 (bs, 1H), 4.69 (t, J = 7.0 Hz, 1H), 4.39-4.30 (m, 1 H) ), 3.89, (s, 3H), 3.14 (dd, J = 15.9, 6.7Hz, 1H), 2.76 (dd = 15.9, 5.1 Hz, 1H), 2.71 (q, = 7.7 Hz, 2H), 1.44 (s) , 9H), 1.24 (t, = 7.6 Hz, 3H).

Compound 21 Trifluoroacetic acid (0.5 ml) was added to a stirring solution of the intermediate (22 mg, 0.04 mmol) in CH2Cl2 (2 mL) at 0 ° C. The ice bath was removed and the reaction was allowed to warm to room temperature for 1 hour. The solvent was removed under reduced pressure and replaced with EtOAc (5 mL). A saturated aqueous solution of NaHCO 3 was added to the organic solution and the diphasic system was stirred vigorously for 30 minutes. The organic layer was separated, dried (Na 2 SO 4), and concentrated under reduced pressure to provide the desired product as an off-white solid (11 mg, 61%). 1 H NMR (300 MHZ, DMSO-de) d 10.1 (s, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.69-7.40 (m, 7H), 7.15-7.11 (m, 2H), 5.73 ( s, 2H), 4.53 (d, J = 5.6 Hz, 1H), 3.83, (s, 3H) 2.85 (d, J = 15.8 Hz, 1H), 2.65 (q, J = 7.5 Hz, 2H), 2.53- 2.44 (m, 1H), 1.16 (t, J = 7.6 Hz, 3H).

Preparation 12 Synthesis of Regioisomers of Compound 4 A solution of concentrated H2SO4 (30 g) and concentrated HN03 (10 g) was added dropwise over 2 hours to a stirring solution of indane (10 g, 81.6 mmol) at -20 ° C. The resulting purple solution was then stirred for a further hour, after which 20 g of water were added dropwise. The organics were extracted with EtOAc (3 x 20 mL), dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (80% hexanes / 20% Et20) of the residue provided a 2: 3 mixture of the two products (5.33 g, 37%) as a viscous oil. This material was used directly in the next step without further purification.

A solution of Cr03 (7.59 g, 75.9 mmol) in 50% aqueous acetic acid (84 ml) was added dropwise to a stirring solution of two nitroindanes (3.0 g, 18.4 mmol) in acetic acid (75 ml) at room temperature. ambient. After the addition, the stirring was continued for a further 24 hours. Then 50 mL of isopropyl alcohol was slowly added and the green mixture was stirred for 30 minutes at room temperature. The organics were extracted with Et2 = (4 x 20 mL), dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (30% EtOAc / 70% hexanes at 50% EtOAc / 50% hexanes) provided three separate compounds in a ratio of 3: 3: 1 (A: B: C) in a combined yield of 22%. 1H NMR of compound A (300 MHZ, CDCI3) d 8.36 (d, J = 2.0 Hz, 1H), 8.25 (dd, J = 7.0.2.0 Hz, 1H), 7.92 (d, = 7.0 Hz, 1H), 3.32 -3.27 (m, 1H), 2.88-2.83 (m, 2H).

Rhodium trichloride (1 mg, cat) was added to a solution of 7-nitroindene (150 mg, 0.93 mmol) in 8 ml of absolute ethanol at room temperature. The resulting solution was heated to reflux for 14 hours, after which the solvent was removed and the residue was purified by flash chromatography (5% Et20 / 95% hexanes) to provide the desired product (64 mg, 43%). %) as a pale brown solid and a starting material (76 mg, 51%). 1 H NMR of the product (300 MHZ, CDCl 3) d 8.15 (d, J = 6.6 Hz, 1H), 7.74-7.70 (m, 2H), 7.34 (t, J = 6.6 Hz, 1H), 6.95-6.90 (m, 1H), 3.54 (s, 2H).

This regioisomer of compound 4 was synthesized following the same general procedure used for the preparation of compound 4. 1 H NMR (300 MHZ, CD30D) d 8.24 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 1.1 Hz, 1H), 7.50-7.36 (m, 6H) 7.09 (dd, J = 8.1.5.1 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 5.10 (bs, 1H), 4.36 (dd, J = 8.1, 5.1 Hz, 1H), 4.10 (q, J = 6.0 Hz, 1H), 3.82 (s, 3H), 3.07 (dd, J = 15.6, 5.8 Hz, 1H), 2.70 (q, = 7.5 Hz, 2H), 2.59 (dd, = 15.6, 5.8 Hz, 1H), 1.23 (t, = 7.5 Hz, 3H).

This regioisomer of compound 4 was synthesized following the same general procedure used for the preparation of compound 4. 1 H NMR (300 MHZ, CDCl 3) d 7.91 (d, J = 8.3 Hz, 3 H), 7.61 (s, 1 H), 7.42- 735 (M, 5H), 7.22 (t, J = 7.9, Hz, 2H), 7.10 (dd, .7 = 7.9, 1.38 Hz, 1H), 6.72 (d, = 7.4 Hz, 1 H), 5.02 (d , = 7.5 Hz, 1H), 4.56-4.51 (m, 2H), 3.87 (s, 3H), 3.38 (s, 1H), 3.25 (dd, = 15.7, 7.7Hz, 1H), 2.81-2.72 (m, 3H), 1.28 (t, J = 7.5 Hz, 3H).

BioEnsays 1. Cloning, construction and testing of CHO cells that express potassium channels fed by human voltage.

Human voltage-fed potassium channels were cloned from genomic HeLa cell DNA through polymerase chain reaction (PCR), sequenced to verify their composition, and then permanently expressed in Chinese Hamster Ovary cell lines (CHO). ) (obtained from ATCC) using methods well known to those skilled in the art. Specifically, HeLa cells (approximately 1000 cells) were washed in pH-regulated saline with phosphate, formed into pellets, and straightened in 50μl of sterile water. PCR reagents including specific end primers were added directly to the lysate and the mixture was subjected to 40 temperature cycles. The reaction products were separated on an agarose gel and a DNA band corresponding to the expected size of the simplified product was isolated and cloned into the cloning vector pCRI1 (Invitrogen). The amplified E. coli construct and a number of independent subclones were isolated and sequenced to verify the identity of the cloned channel. Then, the error-free portions of these were ligated together to form a complete cDNA construct and this construct was subcloned into the eukaryotic expression vector pCDNA3 (Invitrogen). The complete construct contained a Kozak sequence at the beginning to direct protein synthesis. CHO cells were transfected with the construct and stable expression cells were selected including G418 in the culture medium. After 3 weeks, the stably transfected cells were seeded at a limiting density and individual clones were isolated and grown to confluence. Stable clones were tested for voltage-fed potassium channel expression using an 86Rubidium (86Rb) ion flow assay (see below for methodology). In the case of the Kv1.3 potassium channel, four positive clones and one negative control were tested in the Rubidium emanation assay for the inhibition of emanation through margatoxin, a known blocker of Kv 1.3 channels. All the positive clones exhibited an eXavation of 86Rb stimulated by KCl between 7 to 10 times above basal, which was inhibited at a level approximately 95% when margatoxin was present. These clones were tested through electrophysiology, and it was clearly shown that they possess properties consistent with the expression of the potassium channel. 2. Emanation of 86 Rubidium from cell monolayers CHO cells stably transfected with human Kv1.5 or Kv1.3, as well as non-transfected cells, developed at approximately 90% confluency in 24-well tissue culture plates. Then, the tissue culture growth medium was removed and replaced with 1 ml of Iscoves-modified DMEM containing 86Rb at a concentration of 1 μCi / ml and incubated for three hours at 37 ° C to allow intracellular consumption of the isotope . At the end of the incubation period, the 86Rb solution was aspirated and the cells were washed three times with an Earls Balanced Salt Solution (EBSS). The cells were then incubated for 15 minutes at room temperature in 0.06 ml / well of EBSS or EBSS containing the compounds to be tested. At the end of this period, a 0.3 ml sample was taken for analysis to determine the basal emanation of 86Rb. To each cavity was added 0.3 ml of EBSS with a high content of modified KCl, containing 125 ml KCl (NaCl replaced by KCl, final concentration of KCl in each cavity was 65 mM) and the compounds to be tested. The high concentration of KCl was used to depolarize the cells at membrane potential that could activate the Kv1.3 and Kv1.5 channels. After a 15 minute incubation, another 0.3 ml sample was taken for analysis. Finally, 0.3 ml of 0.2% sodium dodecyl sulfate in EBSS was added to each well to smooth the cells. From this lysate, 0.3 ml was taken for analysis to determine the final cell content of 86Rb. The samples were counted in a Wallac Microbeta Liquid Synthesis counter through the Cerenkov emission. The emanation was expressed as a percentage of the initial cell content of 86, Rb. 3. Fluorescent Measurement of the Cell Membrane Potential CHO cells stably transfected with genes encoding human voltage fed potassium channels were grown to 80% / 90% confluence in 96-well tissue culture plates. On the experimental day, they were suddenly contacted with modified EBSS (116 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl2, 0.8 mM MgCl2, 20 mM HEPES, 5 mM glucose, pH 7.4, 300 mOsm) plus 5 μM of voltage sensitive oxonol dye, trimethyl oxonol of bis- (1,3-dibutylbarbituric acid) (diBac4 (3)). Dibac4 (3) binds to intracellular proteins in a membrane-dependent process, changing the effective concentration of fluorescence molecules. An increase in fluorescence is indicative of membrane depolarization, while a reduction in fluorescence indicates membrane hyperpolarization (Epps et al., Chemistry and Physis of Lipids, 69: 137, 1994). The cells in each well were then incubated in EBSS + 5μM Dibac (3) at 37 ° C for 30 minutes. The 96-well plates were then placed in a controlled temperature chamber at 35 ° C in a laser-based fluorescence imaging plate reader (NovelTech Inc.). The data was collected every 60 seconds for periods ranging from 20 to 40 minutes. To allow comparative quantification of the magnitude of changes induced by the drug in the fluorescence signal, changes were compared with the addition of EBSS + 5μM Dibac4 (3) without drug and EBSS + 5μM Dibac4 (3) + 30mM KCl without drug, and were expressed as a percentage of the increase in fluorescence induced by exposure of the cells to 30 mM KCl. (The elevation of extracellular KCl is known to depolarize the cells). For the effective use of Dibac4 (3) in the tests described above, the contact of dye-containing solutions with plastics and proteins was minimized. 4. Electrophysiological Studies Electrophysiological recordings of natural channels were made in cells and cell lines, cloned channels and expressed in cells (for example, CHO cells) as well as isolated cardiac myocytes, using the complete cell configuration of the patch clamping technique (Hamill et al., Pflugers Archiv 39, 85, 1981). The cell lines were prepared as described above (cloning, etc.). Cardiac rat and human myocytes were isolated using the methods described by Castle and Slawsky, J Pharmacol. Exp. Ther, 264: 1450, 1993 and Wang et al., Circ. Res., 73: 1061, 1993, respectively. The cells were plated on glass coverslips at a density of 2 x 10 4 cells / coverslips and used in 24-48 hours for cultured cell lines and in 6 hours for isolated cardiac myocytes. The coverslips were placed in a small chamber (volume ~ 200μl) in the mechanical stage of an inverted microscope and infused (2ml / min) with extracellular recording solution. Drug application was achieved through a series of narrow-hole glass capillary tubes (internal diameter ~ 1 OOμm) placed approximately 200μm from the cells. The application of voltage-clamping pulses, data acquisition and analysis were controlled through a Pentium 75 MHz computer using the pCLAMP 6.0 software (Axon Instruments Inc. Foster City, CA).

. Lymphocyte Proliferation Studies A T lymphocyte proliferation assay was performed using human peripheral T lymphocytes isolated through centrifugation in a lymphocyte separation medium (Organon Teknika) followed by the adhesion of non-T cells on nylon wool. (After isolation, it was found that T lymphocytes have> 98% viability by excluding trypan blue dye). The cells were resuspended in RPMI medium supplemented with 10% fetal bovine serum at a concentration of 1 x 10 6 cells / ml. 100μl of cells / well were supplied to a 96-well plate. The cells were stimulated with phytohemagglutinin (final concentration of 1.25 or 2.5 μg / ml) in the presence or absence of several antagonists for 3 days. On the fourth day, the cells were pulsed with [3 H] thymidine for an additional 18 hours and harvested on glass fiber filter mats with excessive washing. The mats were counted in a Wallac Microbeta liquid scintillation counter using a fusion scintillator. Additional cavities were counted at the end of the 18-hour period to determine if drug treatments caused cellular toxicity.

EXAMPLE 1 Effect of Compound 4 on the membrane potential in cell monolayers The inhibition of voltage-fed potassium channels through compound 4 and related molecules was initially determined through their ability to induce cell membrane depolarization in monolayers of CHO cells permanently transfected with cDNA for human Kv1.5 or Kv1.3 potassium channels. The actions of the compound indane 4 and related molecules were compared with effects of known inhibitors of Kv1.5 or Kv1.3 to alter the membrane potential as detected with the voltage-dependent fluorescent dye Dibac4 normalized to the depolarization induced by 30 mM KCl . By way of example, Figure 1 illustrates the effect of compound 4 on the membrane potential in monolayers of CHO cell expressing human Kv1.3, which at 10 μM, produced a depolarization similar in magnitude to that induced by specific blocking toxin margatoxin of Kv1.3. The values are ± s.e. means of four observations. The addition of agents is indicated by the arrows. The baseline fluorescence is shown through open symbols. Compound 4 that induced polarization was present in non-transfected cells.

EXAMPLE 2 Effect of compound 4 on emanations of 8 a6oR, ubid of cell monolayers expressing Kv1.5 or Kv1.3 The effect of compound 4 on the emanation of 0 86D, Rb from pre-loaded monolayers of CHO cells expressing Kv1.5 or human Kv1.3 is shown in Figure 2. The values are ± se means (n = 4) of the amount of 86Rb released in a period of 15 minutes and expressed as the percentage of the initial cell content. The relationship between the KCl-induced emanation and the activation of Kv1.3 or Kv1.5 is supported by the observation that non-transfected CHO cells did not exhibit an increase in 86Rb emanation in the presence of KCl. The differential effect of 5 nM of margatoxin confirmed the specific activation of the 86Rb emanation channel of CHO cells expressing Kv1.3 or Kv1.5. An increase in the rate of 86Rb emanation after exposure to 60 mM KCl occurred in cells expressing Kv1.5 or Kv1.3, but was absent in non-transfected cells (wild type). In Kv1.3 expression cells, 60 mM KCl produced an increase in the rate of 86Rb emanation, it could be completely avolouted through pre-exposure to either 5 nM margatoxin or 10 μM compound 4. Similarly , 10μM of compound 4 completely inhibited the increase evoked by 60mM KCl at the 86Rb emanation rate in CHO cells expressing Kv1.5.

EXAMPLE 3 Effects of Related Compound 4 and Compound on Kv1.5 and Kv1.3 Potassium Channels Direct measurement of the inhibitory action of Compound 4 and related compounds on ionic currents was measured using the full-cell patch clamping assay as It was described. As an example, the inhibitory action of compound 4 on the ionic currents through the channels Kv1.5 and Kv1.3 in the CHO cells is illustrated in Figure 3. Clamping steps with a voltage of 500 ms from -80mV to + were applied 60mV to individual cells every 20 seconds for Kv1.5 and every 60 seconds for Kv1.3. Current traces recorded in the absence of the drug are shown, after a 5 minute pre-incubation with 10μM of compound 4. The efficacy of compound 4 and the representative structural homologs as Kv1.5 inhibitors are shown in Table 1.

TABLE 1 C om ip 50% Channel Inhibition (IC ^) 4 0.1 μM (approx.) 2 1 μM (approx.) 16 1 μM (approx.) 13 1 μM (approx.) 11 1 μM (approx.) 15 1 μM (approx.) 17 > 1 μM (approx.) 12 > 1 μM (approx.) 10 > 1 μM (approx.) Other compounds illustrated as examples of Formulas (I), (II) and (III) exhibited IC 50 values greater than 5 μM but less than 50 μM.

EXAMPLE 4 Effect of compound 4 on lKur in human atrial myocytes The potassium channel fed by delayed rectifier voltage responsible for the cardiac ionic current variously termed as lKur or lsus is reported to contain the subunit gene product at Kv1.5. lKur (or ISUs) is generally believed to be important in the repolarization of human atrial action potential (Wang et al., Circ Res, 73: 1061, 1993; Fedida et al., Circ Res. 73: 210, 1993 Wang et al., J Pharmacol. Exp. Ther. 272: 184, 1995). It was found that 1 μM of compound 4 inhibits the currents of lKur in human atrial myocytes in a > fifty%.

EXAMPLE 5 Effect of compound 4 on cardiac action potential A functional consequence of the inhibition of the potassium channel in the heart is an extension of the potential duration of action. This increase in the potential duration of the action, and the resulting prolongation of the effective refractory perimeter to propagate the electrical excitation capacity in the heart, mechanically represents antiarrhythmic properties of the agents that block the potassium channels. 1 μM of compound 4 prolongs the action potential by one > 50% in isolated human atrial myocytes. Similarly, Figure 4 shows that 1 μM of compound 4 prolongs the action potential in cardiac rat myocytes.

EXAMPLE 6 Lymphocyte Operation Test of Compound 4 A functional consequence of the inhibition of lKn (Kv1.3) in human lymphocytes is an inhibition of antigen-evoked cell proliferation (Chandy et al., J. Exp. Med. 760 : 369, 1984; Lin et al., J. Exp Med, 177: 637, 1993). Such action could therefore be immunosuppressive, producing therapies for conditions where immune cell activation and proliferation need to be avoided or treated. Compound 4 was treated in an in vitro lymphocyte proliferation assay to determine if its Kv1.3 blocking actions can lead to functional changes in a human cellular system. As shown in Figure 4, margotixin, caribdotoxin, and compound 4 all inhibited lymphocyte proliferation to a similar degree when compared to controls with only PHA. Compound 4 was not toxic to human T lymphocytes, since after 90 hours of exposure to 10 μM of compound 4, no increase in cell viability was present. The principles, preferred embodiments and modes of operation of the present invention have been described in an earlier specification. However, the invention is intended to be protected in the present, it is not constructed as limiting in the particular ways described, since it is considered as illustrative rather than restrictive. Variations and changes can be made by those skilled in the art without departing from the spirit of the invention. Those skilled in the art will recognize variations in the processes as described above and will recognize appropriate modifications based on the foregoing description to make use of the compounds of the invention. In the above specification, the following abbreviations were used: Reagent Designation or Fragment m-CPBA mela-chloroperoxybenzoic acid Acetyl Ac [CH3C (0) -] LC Liquid chromatography THF tetrahydrofuran TLC Thin Layer Chromatography DMF dimethylformamide DMAP for -dimethylaminopyridine TEA triethylamine Methyl ethyl EtOH Ethanol Et20 diethyl ether MeOH methanol EtOAc ethyl acetate pTSA para-toluene sulfonic acid TsOHH20 para-toluenesulfonic acid + water PhMe Toluene 1-PrOH iso-propanol AcOH acetic acid NEt3 triethylamine TFA trifluoroacetic acid (SS) Mn-salem Chloride of (S, S) -N, N'-bis- (3,5-di-éry-butyl-alicidene) -1 , 2-cyclohexanediane-manganese (III) PPNO 4-phenylpyridine N-oxide HOBt 1-hydroxybenzotriazole EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 4-DMAP 4-dimethylaminopyridine NH4OAc Ammonium acetate MeCN acetonitrile BocNCI2? /,? / - tert-butyl dichloro-carbamate DMSO dimethyl sulfoxide Ph3P triphenylphosphine Dibac4 bis- (1,3-dibutylbarbituric acid) trimetin oxonol rt room temperature

Claims

1. A compound that has inhibitory activity of the potassium channel of the formula: wherein R1 is H, alkyl or is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; R2 is selected from the group consisting of an alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; R3 is hydrogen or methyl; R 4 is hydrogen or methyl; X1 is C = 0, C = S, or so2; X2 is C = 0 or S02; Y1 is O, (CHj) p, CH20, HC = CH or NH; wherein p is 0, 1 or 2; Y2 is O, (CH2) q, HC = CH or NH; where q is 0 or 1 Z is H, OR5 or NR6R7; wherein R5 is H, (CH2) m-R8; or C (0) - (CH2) m-R8; m = 1 to 5; R8 is N (R9) 2, N (R9) 3L or C02R9; wherein each R9 is independently selected from H or alkyl; and L is a counterion; R6 is H or alkyl; R7 is H, alkyl or C02R10; where R10 is alkyl; or a pharmaceutically acceptable salt or prodrug thereof as long as Z is H, then X1 and X2 both can not be C = 0, while Y1 is (CH2) P with p = 0, while Y2 is (CH2) q with q = 0, and while R1 and R2 both are methyl.

2. A compound according to claim 1, having potassium channel inhibitory activity, wherein: R3 is hydrogen; X2 is S02; Y2 is (CH2) q where q is 0; R4 is hydrogen; X1 is C = 0; R1 is selected from the group of an optionally substituted aryl and an optionally substituted heteroaryl; R2 is selected from the group of an optionally substituted aryl and an optionally substituted heteroaryl; Y1 is O, (CH2) P, CH20, HC = CH or NH; wherein p is 0, 1 or 2, and Z is H or OR 5, wherein R 5 is H, (CH 2) m-R 8; or C (O) - (CH2) m-R8; = 1 to 5; R8 is N (R9) 2, N (R9) 3L or C02R9; wherein each R9 independently is selected from H or alkyl; and L is a counterion; or a pharmaceutically acceptable salt or prodrug thereof.

3. A compound having potassium channel inhibitory activity of the formula: wherein R 1 is H or an optionally substituted aryl selected from the group phenyl and β-naphthyl; R2 is selected from the group of an optionally substituted phenyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; m is 0 or 1; X is O or S; and Y is selected from one of (CH2) P, (CH20) q and (NH) r; wherein p is 0, 1 or 2; q is 0 or 1, and r is 0 or 1; or a pharmaceutically acceptable salt or prodrug thereof.

4. A compound according to claim 3, having the formula: wherein R1, R2 and p have the same meanings as presented in claim 3; or a pharmaceutically acceptable salt or prodrug thereof.

5. A pharmaceutical composition comprising a compound of the following formula: wherein R1 is H, alkyl or is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; R2 is selected from the group consisting of an alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; R3 is hydrogen or methyl; R 4 is hydrogen or methyl; X1 is C = 0, C = S, or S02; X2 is C = 0 or S02; Y1 is O, (CH2) P, CHzO, HC = CH or NH; wherein p is 0, 1 or 2; Y2 is O, (CH2) q, HC = CH or NH; where q is 0 or 1; Z is H, OR5 or NR6R7; wherein R5 is H, (CH2) m-R8; or C (0) - (CH2) m-R8; m = 1 to 5; R8 is N (R9) 2, N (R9) 3L or C02R9; wherein each R9 is independently selected from H or alkyl; and L is a counterion; R6 is H or alkyl; R7 is H, alkyl or COzR10; where R10 is alkyl. or a pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable diluent or carrier, as long as Z is H, then X1 and X2 both can not be C = 0, while Y1 is (CH2) P with p = 0, while Y2 is (CH2) with q = 0, and while R1 and R2 both are methyl.

6. A pharmaceutical composition comprising a compound of the following formula: wherein, R1 is selected from the group of an optionally substituted aryl and an optionally substituted heteroaryl; R2 is selected from the group of an optionally substituted aryl and an optionally substituted heteroaryl; Y1 is O, (CH2) P, CH20, HC = CH or NH; where p is 0 1 or 2; and Z is H or OR 5, wherein R 5 is H, (CH 2) m-R 8, or C (0) - (CH 2) m-R 8; m = 1 to 5; R8 is N (R9) 2, N (R9) 3L or COzR9; wherein each R9 independently is selected from H or alkyl; and L is a counterion, or a pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable diluent or carrier.

7. A pharmaceutical composition comprising a compound of the following formula: wherein R 1 is H or an optionally substituted aryl selected from the group phenyl and β-naphthyl; R is selected from the group of an optionally substituted phenyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; m is 0 or 1; X is O or S; and Y is selected from one of (CH2) P, (CH20) q and (NH) r; wherein p is 0, 1 or 2; q is 0 or 1, and r is 0 or 1; or a pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable diluent or carrier.

8. A pharmaceutical composition comprising a compound of the following formula: wherein R1, R2, m and p have the meanings presented in claim 7; or a pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable diluent or carrier.

9. A method for inhibiting the transport of potassium through cell membranes having potassium channels comprising exposing a cell membrane having said channels to the presence of a compound of the formula: wherein R1 is H, alkyl or is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; R2 is selected from the group consisting of an alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; R3 is hydrogen or methyl; R 4 is hydrogen or methyl; X1 is C = 0, C = S, or S02; X2 is C = 0 or SOz; Y1 is O, (CH2) P, CH20, HC = CH or NH; wherein p is 0, 1 or 2; Y2 is O, (CH2) q, HC = CH or NH; where q is 0 or 1; Z is H, OR5 or NR6R7; wherein R5 is H, (CH2) m-R8; or C (0) - (CH2) m-R8; m = 1 to 5; R8 is N (R9) 2, N (R9) 3L or C02R9; wherein each R9 is independently selected from H or alkyl; and L is a counterion; R6 is H or alkyl; R7 is H, alkyl or C02R1 °; where R10 is alkyl. or a pharmaceutically acceptable salt or prodrug thereof, said compound being present in an amount effective to block the conductance of said channels.

The method according to claim 9, wherein the potassium channel is a potassium channel fed by voltage.

The method according to claim 10, wherein the potassium channel is selected from a potassium channel responsible for the cardiac IKur potassium current, a potassium channel responsible for the lKn potassium current of the T lymphocyte and channels of Potassium containing one of the subunit gene products at Kv1.5 or Kv1.3.

12. A method for inhibiting the transport of potassium through cell membranes having potassium channels comprising exposing a cell membrane having said channels in the presence of a compound of the formula: wherein, R1 is selected from the group of an optionally substituted aryl and an optionally substituted heteroaryl; R2 is selected from the group of an optionally substituted aryl and an optionally substituted heteroaryl; Y1 is O, (CH2) P, CH20, HC = CH or NH; where p is 0 1 or 2; and Z is H or OR 5, wherein R 5 is H, (CH 2) m-R 8, or C (0) - (CH 2) m-R 8; m = 1 to 5; R8 is N (R9) 2, N (R9) 3L or C02R9; wherein each R9 independently is selected from H or alkyl; and L is a counterion, or a pharmaceutically acceptable salt or drug thereof; said compound being present in an amount effective to block the conductance of said channels.

13. The method of claim 12 wherein the potassium channel is a potassium channel fed by voltage.

The method according to claim 13, wherein the potassium channel is selected from a potassium channel responsible for the cardiac lKur potassium current, a potassium channel responsible for the lKn potassium current of the T lymphocyte and channels of potassium containing one of the subunit gene products at Kv1.5 or Kv1.3.

15. A method for inhibiting the transport of potassium through cell membranes that possess potassium channels comprising exposing a cell membrane possessed by said channels to the presence of a compound of the formula: wherein R 1 is H or an optionally substituted aryl selected from the group phenyl and β-naphthyl; R2 is selected from the group of an optionally substituted phenyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; m is 0 or 1; X is O or S; and Y is selected from one of (CH2) P, (CH20) q and (NH) r; wherein p is 0, 1 or 2; q is 0 or 1, and r is 0 or 1; or a pharmaceutically acceptable salt or prodrug thereof; said compound being present in an effective amount to block the conductivity of said channels.

16. The method of claim 15 wherein the potassium channel is a potassium channel fed by voltage.

The method according to claim 16, wherein the potassium channel is selected from a potassium channel responsible for the cardiac lKur potassium current, a potassium channel responsible for the lKn potassium current of the T lymphocyte and potassium containing one of the subunit gene products at Kv1.5 or Kv1.3.

18. A method for treating cardiac arrhythmias comprising administering to a patient with the need thereof a pharmaceutically effective amount of a compound of the following formula: wherein R1 is H, alkyl or is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; R2 is selected from the group consisting of an alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; R3 is hydrogen or methyl; R 4 is hydrogen or methyl; X1 is C = 0, C = S, or S02; X2 is C = 0 or S02; Y1 is O, (CH2) P, CH20, HC = CH or NH; wherein p is 0, 1 or 2; Y2 is O, (CH2) q, HC = CH or NH; where q is 0 or 1; Z is H, OR5 or NR6R7; wherein R5 is H, (CH2) m-R8; or C (0) - (CH2) m-R8; m = 1 to 5; R8 is N (R9) 2, N (R9) 3L or C02R9; wherein each R9 is independently selected from H or alkyl; and L is a counterion; R6 is H or alkyl; R7 is H, alkyl or C02R10; where R10 is alkyl. or a pharmaceutically acceptable salt or prodrug thereof.

19. A method for treating a cell proliferative disorder comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of the following formula: wherein R1 is H, alkyl or is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; R2 is selected from the group consisting of an alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; R3 is hydrogen or methyl; R 4 is hydrogen or methyl; X1 is C = 0, C = S, or S02; X2 is C = 0 or S02; Y1 is O, (CH2) P, CH20, HC = CH or NH; wherein p is 0, 1 or 2; Y2 is O, (CH2) q, HC = CH or NH; where q is 0 or 1 Z is H, OR5 or NR6R7; wherein R5 is H, (CH2) m-R8; or C (0) - (CH2) m-R, 8 °; m = 1 to 5; R8 is N (R9) 2, N (R9) 3L or C02R9; wherein each R9 is independently selected from H or alkyl; and L is a counterion; R6 is H or alkyl; R7 is H, alkyl or C02R10; where R 0 is alkyl; or a pharmaceutically acceptable salt or prodrug thereof.

20. A method for treating cardiac arrhythmias comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of the following formula: wherein, R1 is selected from the group of an optionally substituted aryl and an optionally substituted heteroaryl; R2 is selected from the group of an optionally substituted aryl and an optionally substituted heteroaryl; Y1 is O, (CH2) P, CH20, HC = CH or NH; where p is 0 1 or 2; and Z is H or OR 5, wherein R 5 is H, (CH 2) m-R 8, or C (0) - (CH 2) m-R 8; m = 1 to 5; R8 is N (R9) 2, N (R9) 3L or C02R9; wherein each R9 independently is selected from H or alkyl; and L is a counterion, or a pharmaceutically acceptable salt or prodrug thereof.

21. A method for treating a cell proliferative disorder comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of the following formula: wherein, R1 is selected from the group of an optionally substituted aryl and a heteroaryl optionally substituted; R2 is selected from the group of an optionally substituted aryl and an optionally substituted heteroaryl; Y1 is O, (CH2) P, CH20, HC = CH or NH; where p is 0 1 or 2; and Z is H or OR 5, wherein R 5 is H, (CH 2) m-R 8, or C (0) - (CH 2) m-R 8; m = 1 to 5; R8 is N (R9) 2, N (R9) 3L or C02R9; wherein each R9 independently is selected from H or alkyl; and L is a counterion, or a pharmaceutically acceptable salt or prodrug thereof.

22. A method for treating cardiac arrhythmias comprising administering to a patient with the need thereof, a pharmaceutically effective amount of a compound of the following formula: wherein R 1 is H or an optionally substituted aryl selected from the group phenyl and β-naphthyl; R2 is selected from the group of an optionally substituted phenyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; m is 0 or 1; X is O or S; and Y is selected from one of (CH2) P, (CH20) q and (NH) r; wherein p is 0, 1 or 2; q is 0 or 1, and r is 0 or 1; or a pharmaceutically acceptable salt or prodrug thereof.

23. A method for treating a cell proliferative disorder that allows a patient with the need thereof to administer a pharmaceutically effective amount of a compound of the following formula: wherein R 1 is H or an optionally substituted aryl selected from the group phenyl and β-naphthyl; R is selected from the group of an optionally substituted phenyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, and an optionally substituted carbocycloalkyl; m is 0 or 1; X is O or S; and Y is selected from one of (CH2) P, (CH20) q and (NH) r; wherein p is 0, 1 or 2; q is 0 or 1, and r is 0 or 1; or a pharmaceutically acceptable salt or prodrug thereof.