Heterocyclic inhibitors of the sodium channel

A compound of Formula II:

• wherein
• R1 is H or optionally substituted C1-C6 alkyl;
• or R1 combines with R2 to form an optionally substituted 5- to 6-membered heterocyclyl;
• or R1 combines with R3 to form an optionally substituted 5- to 6-membered heterocyclyl;
• or R1 combines with R5 to form an optionally substituted 5- to 6-membered heterocyclyl;
• R2 is H or optionally substituted C1-C6 alkyl, or R2 combines with R1 to form an optionally substituted C5-C6 cycloalkyl or an optionally substituted 5- to 6-membered heterocyclyl;
• R3 is H, optionally substituted C1-C6 alkyl, optionally substituted phenyl, or optionally substituted alkaryl;
• or R3 combines with R1 to form an optionally substituted 5- to 6-membered heterocyclyl;
• or R3 combines with R4 to form an optionally substituted substituted C3-C6 cycloalkyl or a carbonyl group;
• or R3 combines with R5 to form an optionally substituted 5- to 6-membered heterocyclyl or an optionally substituted substituted C5-C6 cycloalkyl;
• R4 is H or optionally substituted C1-C6 alkyl;
• or R3 combines with R4 to form an optionally substituted substituted C3-C6 cycloalkyl or a carbonyl group;
• n is 0, 1, or 2;
• each R5, when present, is independently H or optionally substituted C1-C6 alkyl;
• or R5 combines with R1 to form an optionally substituted 5- to 6-membered heterocyclyl;
• or R5 combines with R3 to form an optionally substituted 5- to 6-membered heterocyclyl or an optionally substituted substituted C5-C6 cycloalkyl;
• each R6, when present, is independently H or optionally substituted C1-C6 alkyl;
• R7 is H or optionally substituted C1-C6 alkyl;
• L1 is optionally substituted C1-C6 alkylene;
• and
• Ar is an optionally substituted phenyl;
• or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

A compound of Formula III:

• wherein R1 is selected from hydrogen and optionally substituted C1-C6 alkyl;
• R2 and R3 are independently selected from hydrogen;
• optionally substituted C1-C6 alkyl;
• optionally substituted C3-C6 cycloalkyl;
• and optionally substituted aromatic;
• and
• each of R4, R5, R6, and R7 is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, O-(optionally substituted phenyl), optionally substituted phenyl, —SO2-(optionally substituted phenyl), —SO2-(optionally substituted C1-C6 alkyl), and halogen;
• or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

A compound of Formula IV:

• wherein R1 is selected from hydrogen and optionally substituted C1-C6 alkyl;
• and
• R2 and R3 are independently selected from hydrogen;
• optionally substituted C1-C6 alkyl;
• optionally substituted C3-C6 cycloalkyl;
• and optionally substituted phenyl;
• or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

A compound of Formula V:

• wherein R1 is an optionally substituted C5-C6 heterocylyl or optionally substituted C1-C6 aminoalkyl;
• R2 is hydrogen or optionally substituted C1-C6 alkyl;
• and
• R3, R4, and R5 are independently selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C6-C10 aryl, optionally substituted heteroaryl, and optionally substituted alkaryl;
• or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

A compound of Formula VI:

• wherein R1 is selected from hydrogen and optionally substituted C1-C6 alkyl;
• m is an integer between 0-4
• each R2 is selected, independently, from halogen, CN, NO2, COOR′, CONR′2, OR′, SR′, SOR′, SO2R′, NR′2, NR′(CO)R′, and NR′SO2R′, wherein each R′ is independently H or an optionally substituted group selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 heteroalkyl, C2-C6 heteroalkenyl, and C2-C6 heteroalkynyl;
• or each R2 is independently an optionally substituted group selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 heteroalkyl, C2-C6 heteroalkenyl, or C2-C6 heteroalkynyl;
• or wherein two R2 on the same carbon combine to form ═O and ═NOR;
• and
• R3 and R4 is independently selected from hydrogen;
• optionally substituted C1-C6 alkyl;
• optionally substituted C3-C6 cycloalkyl;
• optionally substituted C3-C6 heterocyclyl;
• SO2R5, wherein R5 is amino, optionally substituted C1-C6 alkyl, or optionally substituted phenyl;
• or R1 and R2 together form an optionally substituted 3- to 7-membered heterocyclyl;
• or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

A compound of Formula VII:

• wherein R1, R2, R3, and R4 is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1 alkoxy, O-(optionally substituted phenyl), optionally substituted phenyl, —SO2-(optionally substituted phenyl), —SO2-(optionally substituted C1-C6 alkyl), and halogen;
• L1 is selected from a covalent bond;
• optionally substituted C1 alkylene;
• and optionally substituted C1 to C3 heteroalkylene;
• R5 together with C(O) is an amino acid residue;
• or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

A compound of Formula VIII:

• wherein Het is an optionally substituted C3-C6 heterocyclyl;
• n is 0 or 1;
• and
• Ar is an optionally substituted phenyl;
• or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

A compound of Formula IX:

• wherein R1 and R2 are independently selected from H, optionally substituted C1-C6 alkyl, and halogen;
• L1 is optionally substituted C1-C6 alkylene;
• m is an integer between 0-4;
• and
• each R3 is selected, independently, from halogen, CN, NO2, COOR′, CONR′2, OR′, SR′, SOR′, SO2R′, NR′2, NR′(CO)R′, and NR′SO2R′, wherein each R′ is independently H or an optionally substituted group selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 heteroalkyl, C2-C6 heteroalkenyl, and C2-C6 heteroalkynyl;
• or each R2 is independently an optionally substituted group selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 heteroalkyl, C2-C6 heteroalkenyl, or C2-C6 heteroalkynyl;
• or wherein two R2 on the same carbon combine to form ═O and ═NOR;
• or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

A compound of Formula X:

• wherein Het is optionally substituted phenyl, optionally substituted pyridine, or optionally substituted benzimidazole;
• R1 is H or optionally substituted C1 to C6 alkyl;
• R2 is H, optionally substituted C1 to C6 alkyl, or optionally substituted C1 to C6 alkoxy;
• R3 is H, optionally substituted C1-C6 alkyl, optionally substituted C1 to C6 alkoxy, or optionally substituted phenyl;
• or R3 combines with R4 to an optionally substituted 5- to 6-membered heterocyclyl;
• R4 is H or optionally substituted C1-C6 alkyl;
• or R4 combines with R5 to form an optionally substituted 5- to 6-membered heterocyclyl;
• or R4 combines with R3 to form an optionally substituted 5- to 6-membered heterocyclyl;
• and
• R5 is H or optionally substituted C1-C6 alkyl, or R5 combines with R4 to form an optionally substituted C5-C6 cycloalkyl or an optionally substituted 5- to 6-membered heterocyclyl;
• or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.