Large-conductance potassium channel modulators, compositions thereof, methods of manufacturing thereof, and methods of use thereof

A method of treating a disease or condition modulated by large-conductance potassium channels comprising administering, to a patient in need thereof, an effective amount of a large-conductance potassium channel modulating compound selected from compound(s) of Formula (I):

• wherein:
• R1 and R2 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl;
• or R1 and R2 combine as to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl;
• R3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR1R2, —C(O)OR1, acyl, or aryl;
• R4 is H, alkyl, or substituted alkyl;
• R5 is H, alkyl, propargylic, substituted propargylic, homopropargylic, substituted homopropargylic, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —OR1, —NR1R2, —C(O)OR1, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic;
• or R3 and R5 combine as to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl;
• R6 is H, alkyl, substituted alkyl or alkenyl;
• X is a bond, O or NR4;
• and,
• Y is N, CR6 or C;
• wherein:
• if Y is N or CR6, then bond b1 is nil and:
• (i) Z is H, bond b2 is a single bond, and A is CH;
• or, (ii) Z is nil, bond b2 is nil, and A is a single bond;
• and,
• if Y is C, then bond b1 is a single bond, and:
• (i) Z is CH2, bond b2 is a single bond, and A is CH;
• or, (ii) Z is CH, bond b2 is a double bond, and A is C;
• or a salt thereof;
• wherein the disease or condition is a cardiac disorder selected from cardiac ischemia or cardiac hypoxia.

A method of treating a disease or condition modulated by large-conductance potassium channels comprising administering, to a patient in need thereof, an effective amount of a large-conductance potassium channel modulating compound selected from compound(s) of Formula (I):

• wherein:
• R1 and R2 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl;
• or R1 and R2 combine as to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl;
• R3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR1R2, —C(O)OR1, acyl, or aryl;
• R4 is H, alkyl, or substituted alkyl;
• R5 is H, alkyl, propargylic, substituted propargylic, homopropargylic, substituted homopropargylic, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —OR1, —NR1R2, —C(O)OR1, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic;
• or R3 and R5 combine as to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl;
• R6 is H, alkyl, substituted alkyl or alkenyl;
• X is a bond, O or NR4;
• and,
• Y is N, CR6 or C;
• wherein:
• if Y is N or CR6, then bond b1 is nil and:
• (i) Z is H, bond b2 is a single bond, and A is CH;
• or, (ii) Z is nil, bond b2 is nil, and A is a single bond;
• and,
• if Y is C, then bond b1 is a single bond, and:
• (i) Z is CH2, bond b2 is a single bond, and A is CH;
• or, (ii) Z is CH, bond b2 is a double bond, and A is C;
• or a salt thereof;
• wherein the disease or condition is a cerebral disorder selected from cerebral ischemia or cerebral hypoxia.