Potassium channel inhibitors

A compound of formula (II) or a pharmaceutically acceptable salt, ester, amide, complex, chelate, hydrate, stereoisomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:

• wherein t is 1, or 2;
• 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 with the proviso that when R1 is an optionally substituted aryl, then R1 is not a dialkoxyphenyl;
• Y2 is (CH2)q(CH2)wO, HC═CH, ethynyl or NH w is 0, 1, or 2 and q is 0, 1, or 2, with the proviso that if Y2 is (CH2)q and q=0, then R1 cannot be H;
• X2 is C═O, C═S, or SO2;
• with the proviso that if Y2 is (CH2)wO then X2 is not SO2;
• R3 is H, alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
• Z is H, OR14, SR14 or NR15R16;
• where R14 is selected from the group consisting of H, (CH2)m—R8, or C(O)—(CH2)r—R8;
• m is 1, 2, 3, or 4;
• r is 0, 1, 2, or 3;
• R8 is CH2N(R9)2, CH2N(R9)3L, or CO2R9;
• each R9 is independently selected from H, or alkyl;
• L is a counter ion;
• R15 is H, or alkyl;
• and R16 is H, alkyl or CO2R10 and R10 is H, or alkyl;
• R2 is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, Ra—O—, and RbRc—N—;
• where Ra and Rb are independently selected from the group consisting of alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted carbocycloalkyl;
• Rc is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted carbocycloalkyl;
• Y1 is (CH2)p, CHR17(CH2)o, HC═CH, or ethynyl;
• where R17 is 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;
• p is 0, 1, 2, or 3;
• and o is 0, 1, or 2;
• X1 is C═O, C═S, SO2or (CH2)n;
• where n is 0, 1, or 2;
• R4 is H, alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
• and
• with the provisos (i) that if Y1 is (CH2)p, p is 0 and X1 is not (CH2)n, then R2 is not H, and (ii) that if R2 is Ra—O— and Y1 is (CH2)p with p=0, then X1 is not SO2.

A compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, complex, chelate, hydrate, stereoisomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:

• wherein t is 1, or 2;
• A and B are each H, or taken together form a bond between the substituted carbons;
• 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 with the proviso that when R1 is an optionally substituted aryl, then R1 is not a dialkoxyphenyl;
• Y2 is (CH2)q, (CH2)wO, HC═CH ethynyl or NH, w is 0, 1, or 2 and q is 0, 1, or 2, with the proviso that if Y2 is (CH2)q and q=0, then R1 cannot be H;
• X2 is C═O, C═S, or SO2;
• with the proviso that if Y2 is (CH2)wO, then X2 is not SO2;
• R3 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• Z is H, alkyl, alkyenyl, alkylene(heterocyclyl), alkylene(heteroaryl), alkylene-NHC(O)(alkyl), alkylene-NHC(O)(aryl), alkylene-NHC(O)(heterocyclyl), alkylene-NHC(O)(heteroaryl), alkylene-NHC(O)-(alkylene-heterocyclyl), alkylene-NHC(O)-(heteroaralkyl), alkylene-C(O)(alkyl), alkylene-C(O)O(alkyl), OR14, SR14 or NR15R16;
• where R14 is selected from the group consisting of H, (CH2)m—R8, or C(O)—CH2)r—R8;
• m is 1, 2, 3, or 4;
• r is 0, 1, 2, or 3;
• R8 is CH2N(R9)2, CH2N(R9)3L, or CO2R9;
• each R9 is independently selected from H, or alkyl;
• L is a counter ion;
• R15 is H, or alkyl;
• and R16 is H, alkyl or CO2R10 and R10 is H, or alkyl;
• R2 is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, an optionally substituted carbocycloalkyl, Ra—O—, and RbRc—N—;
• where Ra and Rb are independently selected from the group consisting of alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• Rc is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• or Rb and Rc along with the nitrogen to which they are attached form a heterocyclyl;
• Y1 is (CH2)p, CHR17(CH2)o, HC═CH, or ethynyl;
• where R17 is 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;
• p is 0, 1, 2 or 3;
• and o is 0, 1 or 2;
• X1 is C═O, C═S, SO2, or (CH2)n;
• where n is 0, 1, or 2;
• R4 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• and
• with provisos (i) that if Y1 is (CH2)p, p is 0 and X1 is not (CH2)n, then R2 is not H, (ii) that if R2 is Ra—O and Y1 is (CH2)p with p=0, then X1 is not SO2 and (iii) if Z is not H, OR14, SR14 or NR15R16, then X2 must be SO2.

A method for inhibiting potassium transport across cellular membranes possessing potassium channels comprising exposing a cell membrane possessing said channels to the presence of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, complex, chelate, hydrate, stereoisomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:

• wherein t is 1, or 2;
• A and B are each H, or taken together form a bond between the substituted carbons;
• 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;
• Y2 is (CH2)q, (CH2)wO, HC═CH, ethynyl or NH, w is 0, 1, or 2 and q is 0, 1, or 2, with the proviso that if Y2 is (CH2)q and q=0, then R1 cannot be H;
• X2 is C═O, C═S, or SO2;
• with the proviso that if Y2 is (CH2)wO, then X2 is not SO2;
• R3 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• Z is H, alkyl, alkyenyl, alkylene(heterocyclyl), alkylene(heteroaryl), alkylene-NHC(O)(alkyl), alkylene-NHC(O)(aryl), alkylene-NHC(O)(heterocyclyl), alkylene-NHC(O)(heteroaryl), alkylene-NHC(O)-(alkylene-heterocyclyl), alkylene-NHC(O)-(heteroaralkyl), alkylene-C(O)(alkyl), alkylene-C(O)O(alkyl), OR14, SR14 or NR15R16;
• where R14 is selected from the group consisting of H, (CH2)m—R8, or C(O)—(CH2)rR8;
• m is 1, 2, 3, or 4;
• r is 0, 1, 2, or 3;
• R8 is CH2N(R9)2, CH2N(R9)3L, or CO2R9;
• each R9 is independently selected from H, or alkyl;
• L is a counter ion;
• R15 is H, or alkyl;
• and R16 is H, alkyl or CO2R10 and R10 is H, or alkyl;
• R2 is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, an optionally substituted carbocycloalkyl, Ra—O—, and RbRc—N—;
• where Ra and Rb are independently selected from the group consisting of alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• Rc is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• or Rb and Rc along with the nitrogen to which they are attached form a heterocyclyl;
• Y1 is (CH2)p, CHR17(CH2)o, HC═CH, or ethynyl;
• where R17 is 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;
• p is 0, 1, 2 or 3;
• and o is 0, 1 or 2;
• X1 is C═O, C═S, SO2or (CH2)n;
• where n is 0, 1, or 2;
• R4 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• and
• with the provisos (i) that if Y1 is (CH2)p, p is 0 and X1 is not (CH2)n, then R2 is not H, (ii) that if R2 is Ra—O and Y1 is (CH2)p with p=0, then X1 is not SO2, and (iii) if Z is not H, OR14, SR14 or NR15R16, then X2 must be SO2.

A method for inhibiting potassium transport across cellular membranes possessing potassium channels comprising exposing a cell membrane possessing said channels to the presence of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, complex, chelate, hydrate, stereoisomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug:

• wherein t is 1, or 2;
• A and B are each H;
• 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;
• Y2 is (CH2)q, HC═CH, or ethynyl and q is 0, 1, or 2, with the proviso that when Y2 is (CH2)q and q=0, then R1 cannot be H;
• X2 is SO2;
• R3 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• Z is H, alkyl, alkyenyl, alkylene(heterocyclyl), alkylene(heteroaryl), alkylene-NHC(O)(alkyl), alkylene-NHC(O)(aryl), alkylene-NHC(O)(heterocyclyl), alkylene-NHC(O)(heteroaryl), alkylene-NHC(O)-(alkylene-heterocyclyl), alkylene-NHC(O)-heteroaryl), alkylene-C(O)(alkyl), alkylene-C(O)O(alkyl), OR14, SR14 or NR15R16;
• where R14 is selected from the group consisting of H, (CH2)m—R8, or C(O)—(CH2)r—R8;
• m is 1, 2, 3, or 4;
• r is 0, 1, 2, or 3;
• R8 is CH2N(R9)2, CH2N(R9)3L, or CO2R9;
• each R9 is independently selected from H, or alkyl;
• L is a counter ion;
• R15 is H, or alkyl;
• and R16 is H, alkyl or CO2R10 and R10 is H, or alkyl;
• R2 is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, an optionally substituted carbocycloalkyl, Ra—O—, and RbRc—N—;
• where Ra and Rb are independently selected from the group consisting of alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• Rc is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• or Rb and Rc along with the nitrogen to which they are attached form a heterocyclyl;
• Y1 is (CH2)p, CHR17(CH2)o, HC═CH, or ethynyl;
• where R17 is 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;
• p is 0, 1, 2 or 3;
• and o is 0, 1 or 2;
• X1 is C═O, C═S, or (CH2)n;
• where n is 0, 1, or 2;
• R4 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• and
• with the provisos (i) that when Y1 is (CH2)p, p is 0 and X1 is not (CH2)n, then R2 is not H, and (ii) that if R2 is Ra—O and Y1 is (CH2)p with p=0, then X1 is not SO2.

A method for inhibiting potassium transport across cellular membranes possessing potassium channels comprising exposing a cell membrane possessing said channels to the presence of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, complex, chelate, hydrate, stereoisomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug:

• wherein t is 1, or 2;
• A and B are each H;
• 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;
• Y2 is (CH2)q and q is 0, 1, or 2, with the proviso that when q=0, then R1 cannot be H;
• X2 is SO2;
• R3 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• Z is H, alkyl, alkyenyl, alkyleneheterocyclyl), alkylene(heteroaryl), alkylene-NHC(O)(alkyl), alkylene-NHC(O)(aryl), alkylene-NHC(O)(heterocyclyl), alkylene-NHC(O)(heteroaryl), alkylene-NHC(O)-(alkylene-heterocyclyl), alkylene-NHC(O)-(heteroaralkyl), alkylene-C(O)(alkyl), alkylene-C(O)O(alkyl), OR14, SR14 or NR15R16;
• where R14 is selected from the group consisting of H, (CH2)m—R8, or C(O)—(CH2)r—R8;
• m is 1, 2, 3, or 4;
• r is 0, 1, 2, or 3;
• R8 is CH2N(R9)2, CH2N(R9)3L, or CO2R9;
• each R9 is independently selected from H, or alkyl;
• L is a counter ion;
• R15 is H, or alkyl;
• and R16 is H, alkyl or CO2R10 and R10 is H, or alkyl;
• R2 is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, an optionally substituted carbocycloalkyl, Ra—O—, and RbRc—N—;
• where Ra and Rb are independently selected from the group consisting of alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• Rc is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• or Rb and Rc along with the nitrogen to which they are attached form a heterocyclyl;
• Y1 is (CH2)p, CHR17(CH2)o, HC═CH, or ethynyl;
• where R17 is 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;
• p is 0, 1, 2 or 3;
• and o is 0, 1 or 2;
• X1 is C═O, or (CH2)n;
• where n is 0, 1, or 2;
• R4 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• and
• with the proviso that when Y1 is (CH2)p and p is 0, then R2 is not H.

A method for inhibiting potassium transport across cellular membranes possessing potassium channels comprising exposing a cell membrane possessing said channels to the presence of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, complex, chelate, hydrate, stereoisomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:

• wherein t is 1;
• A and B are each H;
• R1 is 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;
• Y2 is (CH2)q and q is 0;
• X2 is SO2;
• R3 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• Z is H, alkyl, alkyenyl, alkylene(heterocyclyl), alkylene(heteroaryl), alkylene-NHC(O)(alkyl), alkylene-NHC(O)(aryl), alkylene-NHC(O)(heterocyclyl), alkylene-NHC(O)(heteroaryl), alkylene-NHC(O)-(alkylene-heterocyclyl), alkylene-NHC(O)-(heteroaralkyl), alkylene-C(O)(alkyl), alkylene-C(O)O(alkyl), OR14, SR14 or NR15R16;
• where R14 is selected from the group consisting of H, (CH2)m—R8, or C(O)—(CH2)r—R8;
• m is 1, 2, 3, or 4;
• r is 0, 1, 2, or 3;
• R8 is CH2N(R9)2, CH2N(R9)3L, or CO2R9;
• each R9 is independently selected from H, or alkyl;
• L is a counter ion;
• R15 is H, or alkyl;
• and R16 is H, alkyl or CO2R10 and R10 is H, or alkyl;
• R2 is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, an optionally substituted carbocycloalkyl, Ra—O—, and RbRc—N—;
• where Ra and Rb are independently selected from the group consisting of alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• Rc is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• or Rb and Rc along with the nitrogen to which they are attached form a heterocyclyl;
• Y1 is (CH2)p, CHR17(CH2)o, HC═CH, or ethynyl;
• where R17 is 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;
• p is 0, 1, 2 or 3;
• and o is 0, 1 or 2;
• X1 is C═O, or (CH2)n;
• where n is 0, 1, or 2;
• R4 is H alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• and
• with the proviso that when Y1 is (CH2)p and p is 0, then R2 is not H.

A method for treating cardiac arrhythmias which comprises administering to a patient in need thereof, a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, complex, chelate, hydrate, stereoisomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:

• wherein t is 1, or 2;
• A and B are each H, or taken together form a bond between the substituted carbons;
• 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;
• Y2 is (CH2)q, (CH2)wO, HC═CH, ethynyl or NH w is 0, 1, or 2 and q is 0, 1, or 2, with the proviso that if Y2 is (CH2)q and q=0, then R1 cannot be H;
• X2 is C═O, C═S, or SO2;
• with the proviso that if Y2 is (CH2)wO, then X2 is not SO2;
• R3 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• Z is H, alkyl, alkyenyl, alkylene(heterocyclyl), alkylene(heteroaryl), alkylene-NHC(O)(alkyl), alkylene-NHC(O)(aryl), alkylene-NHC(O)(heterocyclyl), alkylene-NHC(O)(heteroaryl), alkylene-NHC(O)-(alkylene-heterocyclyl), alkylene-NHC(O)-(heteroaralkyl), alkylene-C(O)(alkyl), alkylene-C(O)O(alkyl), OR14, SR14 or NR15R16;
• where R14 is selected from the group consisting of H, (CH2)m—R8, or C(O)—(CH2)r—R8;
• m is 1, 2, 3, or 4;
• r is 0, 1, 2, or 3;
• R8 is CH2N(R9)2, CH2N(R9)3L, or CO2R9;
• each R9 is independently selected from H, or alkyl;
• L is a counter ion;
• R15 is H, or alkyl;
• and R16 is H, alkyl or CO2R10 and R10 is H, or alkyl;
• R2 is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, an optionally substituted carbocycloalkyl, Ra—O—, and RbRc—N—;
• where Ra and Rb are independently selected from the group consisting of alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• Rc is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• or Rb and Rc along with the nitrogen to which they are attached form a heterocyclyl;
• Y1 is (CH2)p, CHR17(CH2)o, HC═CH, or ethynyl;
• where R17 is 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;
• p is 0, 1, 2 or 3;
• and o is 0, 1 or 2;
• X1 is C═O, C═S, SO2or (CH2)n;
• where n is 0, 1, or 2;
• R4 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• and
• with the provisos (i) that if Y1 is (CH2)p, p is 0 and X1 is not (CH2)n, then R2 is not H, (ii) that if R2 is Ra—O and Y1 is (CH2)p with p=0, then X1 is not SO2 and (iii) if Z is not H, OR14, SR14 or NR15R16, then X2 must be SO2.

A method for treating cardiac arrhythmias which comprises administering to a patient in need thereof, a pharmaceutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, ester, amide, complex, chelate, hydrate, stereoisomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:

• wherein t is 1, or 2;
• A and B are each H;
• 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;
• Y2 is (CH2)q, HC═CH, or ethynyl and q is 0, 1, or 2, with the proviso that when Y2 is (CH2)q and q=0, then R1 cannot be H;
• X2 is SO2;
• R3 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• Z is H, alkyl, alkyenyl, alkylene(heterocyclyl), alkylene(heteroaryl), alkylene-NHC(O)(alkyl), alkylene-NHC(O)(aryl), alkylene-NHC(O)(heterocyclyl), alkylene-NHC(O)(heteroaryl), alkylene-NHC(O)-(alkylene-heterocyclyl), alkylene-NHC(O)-(heteroaralkyl), alkylene-C(O)(alkyl), alkylene-C(O)O(alkyl), OR14, SR14 or NR15R16;
• where R14 is selected from the group consisting of H, (CH2)m—R8, or C(O)—(CH2)r—R8;
• m is 1, 2, 3, or 4;
• r is 0, 1, 2, or 3;
• R8 is CH2N(R9)2, CH2N(R9)3L, or CO2R9;
• each R9 is independently selected from H, or alkyl;
• L is a counter ion;
• R15 is H, or alkyl;
• and R16 is H, alkyl or CO2R10 and R10 is H, or alkyl;
• R2 is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, an optionally substituted carbocycloalkyl, Ra—O—, and RbRc—N—;
• where Ra and Rb are independently selected from the group consisting of alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• Rc is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• or Rb and Rc along with the nitrogen to which they are attached form a heterocyclyl;
• Y1 is (CH2)p, CHR17(CH2)o, HC═CH, or ethynyl;
• where R17 is 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;
• p is 0, 1, 2 or 3;
• and o is 0, 1 or 2;
• X1 is C═O, C═S, or (CH2)n;
• where n is 0, 1, or 2;
• R4 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• and
• with the provisos (i) that when Y1 is (CH2)p, p is 0 and X1 is not (CH2)n, then R2 is not H, and (ii) that if R2 is Ra—O and Y1 is (CH2)p with p=0, then X1 is not SO2.

A method for treating cardiac arrhythmias which comprises administering to a patient in need thereof, a pharmaceutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt, ester, amide, complex, chelate, hydrate, stereoisomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:

• wherein t is 1, or 2;
• A and B are each H;
• 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;
• Y2 is (CH2)q and q is 0, 1, or 2, with the proviso that when q=0, then R1 cannot be H;
• X2 is SO2;
• R3 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• Z is H, alkyl, alkyenyl, alkyleneheterocyclyl), alkylene(heteroaryl), alkylene-NHC(O)(alkyl), alkylene-NHC(O)(aryl), alkylene-NHC(O)(heterocyclyl), alkylene-NHC(O)(heteroaryl), alkylene-NHC(O)-(alkylene-heterocyclyl), alkylene-NHC(O)-(heteroaralkyl), alkylene-C(O)(alkyl), alkylene-C(O)O(alkyl), OR14, SR14 or NR15R16;
• where R14 is selected from the group consisting of H, (CH2)m—R8, or C(O)—(CH2)r—R8;
• m is 1, 2, 3, or 4;
• r is 0, 1, 2, or 3;
• R8 is CH2N(R9)2, CH2N(R9)3L, or CO2R9;
• each R9 is independently selected from H, or alkyl;
• L is a counter ion;
• R15 is H, or alkyl;
• and R16 is H, alkyl or CO2R10 and R10 is H, or alkyl;
• R2 is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, an optionally substituted carbocycloalkyl, Ra—O—, and RbRc—N—;
• where Ra and Rb are independently selected from the group consisting of alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• Rc is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• or Rb and Rc along with the nitrogen to which they are attached form a heterocyclyl;
• Y1 is (CH2)p, C═O, (CH2)o;
• HC═CH, or ethynyl;
• where R17 is 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;
• p is 0, 1, 2 or 3;
• and o is 0, 1 or 2;
• X1 is C═O, or (CH2)n;
• where n is 0, 1, or 2;
• R4 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• and
• with the proviso that when Y1 is (CH2)p and p is 0, then R2 is not H.

A method for treating cardiac arrhythmias which comprises administering to a patient in need thereof, a pharmaceutically effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt, ester, amide, complex, chelate, hydrate, stereoisomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:

• wherein t is 1;
• A and B are each H;
• R1 is 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;
• Y2 is (CH2)q and q is 0;
• X2 is SO2;
• R3 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• Z is H, alkyl, alkyenyl, alkylene(heterocyclyl), alkylene(heteroaryl), alkylene-NHC(O)(alkyl), alkylene-NHC(O)(aryl), alkylene-NHC(O)(heterocyclyl), alkylene-NHC(O)(heteroaryl), alkylene-NHC(O)-(alkylene-heterocyclyl), alkylene-NHC(O)-(heteroaralkyl), alkylene-C(O)(alkyl), alkylene-C(O)O(alkyl), OR14, SR14 or NR15R16;
• where R14 is selected from the group consisting of H, (CH2)m—R8, or C(O)—(CH2)r—R8;
• m is 1, 2, 3, or 4;
• r is 0, 1, 2, or 3;
• R8 is CH2N(R9)2, CH2N(R9)3L, or CO2R9;
• each R9 is independently selected from H, or alkyl;
• L is a counter ion;
• R15 is H, or alkyl;
• and R16 is H, alkyl or CO2R10 and R10 is H, or alkyl;
• R2 is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, an optionally substituted carbocycloalkyl, Ra—O—, and RbRc—N—;
• where Ra and Rb are independently selected from the group consisting of alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• Rc is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• or Rb and Rc along with the nitrogen to which they are attached form a heterocyclyl;
• Y1 is (CH2)p, CHR17(CH2)o, HC═CH, or ethynyl;
• where R17 is 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;
• p is 0, 1, 2 or 3;
• and o is 0, 1 or 2;
• X1 is C═O, or (CH2)n;
• where n is 0, 1, or 2;
• R4 is H, alkyl an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• and
• with the proviso that when Y1 is (CH2)p and p is 0, then R2 is not H.

A compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, complex, chelate, hydrate, stereoisomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:

• wherein t is 1, or 2;
• A and B are each H or taken together form a bond between the substituted carbons;
• 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 with the proviso that when R1 is an optionally substituted aryl, then R1 is not a dialkoxyphenyl;
• Y2 is (CH2)q, HC═CH, ethynyl or NH q is 0, 1, or 2, with the proviso that if Y2 is (CH2)q and q=0, then R1 cannot be H;
• X2 is SO2;
• R3 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• Z is H, alkyl, alkyenyl, alkylene(heterocyclyl), alkylene(heteroaryl), alkylene-NHC(O)(alkyl), alkylene-NHC(O)(aryl), alkylene-NHC(O)(heterocyclyl), alkylene-NHC(O)(heteroaryl), alkylene-NHC(O)-(alkylene-heterocyclyl), alkylene-NHC(O)-(heteroaralkyl), alkylene-C(O)(alkyl), alkylene-C(O)O(alkyl), OR14, SR14or NR15R16;
• where R14 is selected from the group consisting of H, (CH2)m—R8, or C(O)—(CH2)r—R8;
• m is 1, 2, 3, or 4;
• r is 0, 1, 2, or 3;
• R8 is CH2N(R9)2, CH2N(R9)3L, or CO2R9;
• each R9 is independently selected from H, or alkyl;
• L is a counter ion;
• R15 is H, or alkyl;
• and R16 is H, alkyl or CO2R10 and R10 is H, or alkyl;
• R2 is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, an optionally substituted carbocycloalkyl, Ra—O—, and RbRc—N—;
• where Ra and Rb are independently selected from the group consisting of alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• Rc is selected from the group consisting of H, alkyl, an optimally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl;
• or Rb and Rc along with the nitrogen to which they are attached form a heterocyclyl;
• Y1 is (CH2)p, CHR17(CH2)o, HC═CH, or ethynyl;
• where R17 is 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;
• p is 0, 1, 2 or 3;
• and o is 0, 1 or 2;
• X1 is C═O, C═S, SO2 or (CH2)n;
• where n is 0, 1, or 2;
• R4 is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl;
• an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
• and
• with the provisos (i) that if Y1 is (CH2)p, p is 0 and X1 is not (CH2)n, then R2 is not H;
• and
• (ii) that if R2 is Ra—O and Y1 is (CH2)p with p=0, then X1 is not SO2.