Aryl substituted pyrazoles, triazoles and tetrazoles, and the use thereof

A compound of Formula I:

• 12
• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein
• X is O or S;
• Het is a heteroaryl selected from the group consisting of
• 13
• R1 is C(O)R10, CH2C(O)R10, or SO2R10 wherein R10 is amino, alkyl, N-morpholinyl, N-pyrrolidinyl or N-piperazinyl, all of which can be optionally substituted;
• R2 and R3 are independently hydrogen, C1-C6 alkyl, C1-C6 alkylthio or C1-C6 alkylsulfinyl;
• R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, halo, halo(C1-C6)alkyl, C1-C6 alkyl, hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, carboxy(C1-C6)alkyl, alkoxy(C1-C6)alkyl, nitro, amino, C1-C6 acylamino, amide, hydroxy, thiol, C1-C6 acyloxy, C1-C6 alkoxy, carboxy, carbonylamido and C1-C6 alkylthiol;
• provided that:
• 1) when Het is (ii), and X is O, then R10 is not alkyl, aralkyl, aryl or OR11;
• and
• 2) when Het is (iii), and X is O, then R10 is not OR11.

A method of treating a disorder responsive to the blockade of sodium channels in a mammal suffering therefrom, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I:

• 14
• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein
• X is one of O, S, NR9, CH2, NR9C(O), or C(O)NR9, where R9 is hydrogen or C1-C10 alkyl;
• Het is a heteroaryl selected from the group consisting of
• 15
• R1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroaryl, C(O)R10, CH2C(O)R10, S(O)R10, and SO2R10;
• R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cyano, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxyalkyl, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, alkylcarbonyl, aminosulfonyl, alkylaminosulfonyl, and alkylsulfonyl;
• R5, R6, R7, and R8 are independently selected from the group consisting of hydrogen, halo, haloalkyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;
• R10 is selected from the group consisting of amino, alkyl, alkenyl, alkynyl, OR11, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, cycloalkyl, heterocycle, heteroaryl, aryl, aralkyl, arylalkenyl, arylalkynyl, and cycloalkylalkylamino;
• R11 is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkalimetal.

A method for treating, preventing or ameliorating neuronal loss following global and focal ischemia;

• treating, preventing or ameliorating neurodegenerative conditions;
• treating, preventing or ameliorating pain or tinnitus;
• treating, preventing or ameliorating manic depression;
• providing local anesthesia;
• or treating arrhythmias, or treating convulsions, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I:
• 16
• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein
• X is one of O, S, NR9, CH2, NR9C(O), or C(O)NR9, where R9 is hydrogen or C1-C10 alkyl;
• Het is a heteroaryl selected from the group consisting of
• 17
• R1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroaryl, C(O)R10, CH2C(O)R10, S(O)R10, and SO2R10;
• R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cyano, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxyalkyl, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, alkylcarbonyl, aminosulfonyl, alkylaminosulfonyl, and alkylsulfonyl;
• R5, R6, R7, and R8 are independently selected from the group consisting of hydrogen, halo, haloalkyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;
• R10 is selected from the group consisting of amino, alkyl, alkenyl, alkynyl, OR11, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, cycloalkyl, heterocycle, heteroaryl, aryl, aralkyl, arylalkenyl, arylalkynyl, and cycloalkylalkylamino;
• R11 is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkalimetal.

A compound of Formula I:

• 18
• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein
• X is O or S;
• Het is a heteroaryl selected from the group consisting of
• 19
• R1 is C(O)R10, wherein R10 is amino, N-morpholinyl, N-pyrrolidinyl or N-piperazinyl, all of which can be optionally substituted
• R2 and R3 are independently hydrogen, C1-C6 alkyl, C1-C6 alkylthio or C1-C6 alkylsulfinyl;
• R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, halo, halo(C1-C6)alkyl, C1-C6 alkyl, hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, carboxy(C1-C6)alkyl, alkoxy(C1-C6)alkyl, nitro, amino, C1-C6 acylamino, amide, hydroxy, thiol, C1-C6 acyloxy, C1-C6 alkoxy, carboxy, carbonylamido and C1-C6 alkylthiol.