Aryl substituted pyrazoles, and pyrroles, and the use thereof

The compound having Formula III:

• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein
• Het3 is (i)3 or (ii)3;
• R′1 is C(O)R14;
• R′2 is attached to a carbon atom that is not the linking atom attached to the aryl group and is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cyano, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxyalkyl, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, alkylcarbonyl, heterocyclocarbonyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonyl, and heterocyclosulfonyl;
• R′5, R′6, and R′10 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;
• R′9 is selected from the group consisting of halo, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;
• R14 is selected from the group consisting of amino, alkyl, alkenyl, alkynyl, OR16, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, cycloalkyl, aralkyl, aryl, heteroaryl, arylalkenyl, arylalkenyl, heterocycle, heterocycloalkyl, and cycloalkylalkylamino, all of which can be optionally substituted;
• wherein
• R16 is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkalimetal;
• and
• X is one of O, S, NR15, NR15C(O), or C(O)NR15 where R15 is hydrogen, alkyl or cycloalkyl.

The compound having Formula III:

• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein
• Het3 is (vi)3;
• R′1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroaryl, C(O)R14, CH2C(O)R14, S(O)R14, and SO2R14;
• R′2 is attached to a carbon atom that is not the linking atom attached to the aryl group and is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cyano, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxyalkyl, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, alkylcarbonyl, heterocyclocarbonyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonyl, and heterocyclosulfonyl;
• R′5, R′6, and R′10 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;
• R′9 is selected from the group consisting of halo, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;
• R14 is selected from the group consisting of amino, alkyl, alkenyl, alkynyl, OR16, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, cycloalkyl, aralkyl, aryl, heteroaryl, arylalkenyl, arylalkenyl, heterocycle, heterocycloalkyl, and cycloalkylalkylamino, all of which can be optionally substituted;
• wherein
• R16 is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkalimetal;
• and
• X is one of O, S, NR15, NR15C(O), or C(O)NR15 where R15 is hydrogen, alkyl or cycloalkyl.

The compound having the formula:

• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
• Het is a heteroaryl selected from the group consisting of
• R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, C(O)R14, CH2C(O)R14, S(O)R14, and SO2R14 all of which may be optionally substituted;
• R2, R3, and R4 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxyalkyl, cyano, amino, alkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, alkylcarbonyl, heterocyclocarbonyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonyl, and heterocyclosulfonyl, or the R groups in adjacent carbon atoms can be taken together with the carbon atoms to which they are attached to form a carbocycle or a heterocycle;
• R5, R6, R7, R8, R9, R10, R11, R12, and R13 are independently selected from the group consisting of hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;
• or R9 and R10 or R10 and R11 are taken together with the carbon atoms to which they are attached to form a carbocycle or a heterocycle;
• R14 is selected from the group consisting of amino, alkyl, alkenyl, alkynyl, OR16, alkylamino, dialkylamino, alkenylamino, cycloalkyl, aralkyl, aryl, heteroaryl, arylalkenyl, arylalkynyl, arylalkylamino, dialkylaminoalkenyl, heterocycle, heterocycloalkylamino, and cycloalkylalkylamino, all of which can be optionally substituted;
• wherein
• R16 is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkalimetal;
• and
• X is one of O, S, NR15, CH2, NR15C(O), or C(O)NR15, wherein R15 is hydrogen, alkyl or cycloalkyl,
• wherein said compound is 3H or 14C radiolabeled.

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:

• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
• Het is a heteroaryl selected from the group consisting of
• R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, C(O)R14, CH2C(O)R14, S(O)R14, and SO2R14 all of which may be optionally substituted;
• R2, R3, and R4 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxyalkyl, cyano, amino, alkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, alkylcarbonyl, heterocyclocarbonyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonyl, and heterocyclosulfonyl, or the R groups in adjacent carbon atoms can be taken together with the carbon atoms to which they are attached to form a carbocycle or a heterocycle;
• R5, R6, R7, R8, R9, R10, R11, R12, and R13 are independently selected from the group consisting of hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;
• or R9 and R10 or R10 and R11 are taken together with the carbon atoms to which they are attached to form a carbocycle or a heterocycle;
• R14 is selected from the group consisting of amino, alkyl, alkenyl, alkynyl, OR16, alkylamino, dialkylamino, alkenylamino, cycloalkyl, aralkyl, aryl, heteroaryl, arylalkenyl, arylalkynyl, arylalkylamino, dialkylaminoalkenyl, heterocycle, heterocycloalkylamino, and cycloalkylalkylamino, all of which can be optionally substituted;
• wherein
• R16 is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkalimetal;
• and
• X is one of O, S, NR15, CH2, NR15C(O), or C(O)NR15, wherein R15 is hydrogen, alkyl or cycloalkyl.

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 formula:
• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
• Het is a heteroaryl selected from the group consisting of
• R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, C(O)R14, CH2C(O)R14, S(O)R14, and SO2R14 all of which may be optionally substituted;
• R2, R3, and R4 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxyalkyl, cyano, amino, alkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, alkylcarbonyl, heterocyclocarbonyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonyl, and heterocyclosulfonyl, or the R groups in adjacent carbon atoms can be taken together with the carbon atoms to which they are attached to form a carbocycle or a heterocycle;
• R5, R6, R7, R8, R9, R10, R11, R12, and R13 are independently selected from the group consisting of hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroalyalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;
• or R9 and R10 or R10 and R11 are taken together with the carbon atoms to which they are attached to form a carbocycle or a heterocycle;
• R14 is selected from the group consisting of amino, alkyl, alkenyl, alkynyl, OR16, alkylamino, dialkylamino, alkenylamino, cycloalkyl, aralkyl, aryl, heteroaryl, arylalkenyl, arylalkynyl, arylalkylamino, dialkylaminoalkenyl, heterocycle, heterocycloalkylamino, and cycloalkylalkylamino, all of which can be optionally substituted;
• wherein
• R16 is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkalimetal;
• and
• X is one of O, S, NR15, CH2, NR15C(O), or C(O)NR15, wherein R15 is hydrogen, alkyl or cycloalkyl.

A method of alleviating or preventing seizure activity in an animal subject, comprising administering to said animal in need of such treatment an effective amount of a compound of formula:

• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
• Het is a heteroaryl selected from the group consisting of
• R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, C(O)R14, CH2C(O)R14, S(O)R14, and SO2R14 all of which may be optionally substituted;
• R2, R3, and R4 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxyalkyl, cyano, amino, alkylamino, aminocarbonyl, alkylaminocarbonyl., arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, alkylcarbonyl, heterocyclocarbonyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonyl, and heterocyclosulfonyl, or the R groups in adjacent carbon atoms can be taken together with the carbon atoms to which they are attached to form a carbocycle or a heterocycle;
• R5, R6, R7, R8, R9, R10, R11, R12, and R13 are independently selected from the group consisting of hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylakyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;
• or R9 and R10 or R10 and R11 are taken together with the carbon atoms to which they are attached to form a carbocycle or a heterocycle;
• R14 is selected from the group consisting of amino, alkyl, alkenyl, alkynyl, OR16, alkylamino, dialkylamino, alkenylamino, cycloalkyl, aralkyl, aryl, heteroaryl, arylalkenyl, arylalkynyl, arylalkylamino, dialkylaminoalkenyl, heterocycle, heterocycloalkylamino, and cycloalkylalkylamino, all of which can be optionally substituted;
• wherein
• R16 is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkalimetal;
• and
• X is one of O, S, NR15, CH2, NR15C(O), or C(O)NR15, wherein R15 is hydrogen, alkyl or cycloalkyl.