N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels

A compound of formula (I-A-2):

• or a pharmaceutically acceptable salt thereof, wherein:
• Rd is (CH2)m(CHRe)n(CH2)pH;
• m, n, and p are each independently 0 or 1;
• Re is H, OH, halo, C1-C6 alkoxy, or C1-C6 haloalkoxy;
• R4b1 and R4b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl;
• R5b1 and R5b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl;
• R2c is H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L1-L2-(C3-C6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo;
• L1 is a bond or O;
• L2 is a bond or C1-C6 alkylene;
• R3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl;
• or
• R2c and R3c, together with the carbon atoms to which they are attached, form a ring of formula:
• Z1 and Z2 are each independently O or CH2;
• each R is independently H or halo;
• and
• R4c is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

A compound of formula (I-A):

• or a pharmaceutically acceptable salt thereof, wherein:
• X2a is N, N+—O−, or C—R2a;
• X3a is N+—O−;
• X5a is N, N+—O−, or C—R5a;
• X6a is N, N+—O−, or C—R6a;
• Rd is (CH2)m(CHRe)n(CH2)pH;
• m, n, and p are each independently 0 or 1;
• Re is H, OH, halo, C1-C6 alkoxy, or C1-C6 haloalkoxy;
• R2a and R6a are each independently H, halo, C1-C6 alkyl, or C1-C6 haloalkyl;
• R5a is H, halo, CH2OH, C1-C6 alkyl, or C1-C6 haloalkyl;
• R4b1 and R4b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl;
• R5b1 and R5b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl;
• X3c is N or C—R3c;
• X4c is N or C—R4c;
• X5c is N or C—R5c;
• X6c is N or C—R6c;
• R2c is H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L1-L2-(C3-C6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo;
• L1 is a bond or O;
• L2 is a bond or C1-C6 alkylene;
• R3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl;
• or
• X3c is C—R3c, and R2c and R3c, together with the carbon atoms to which they are attached, form a ring of formula:
• Z1 and Z2 are each independently O or CH2;
• each R is independently H or halo;
• R4c is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
• R5c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl;
• and
• R6c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl;
• provided that no more than two of X2a X3a X5a, and X6a are N or N+—O−;
• and
• provided that no more than one of X3c, X4c, X5c, and X6c is N.

A compound of formula (I-A):

• or a pharmaceutically acceptable salt thereof, wherein:
• X2a is N, N+—O−, or C—R2a;
• X3a is N;
• X6a is N, N+—O−, or C—R6a;
• Rd is (CH2)m(CHRe)n(CH2)pH;
• m, n, and p are each independently 0 or 1;
• Re is H, OH, halo, C1-C6 alkoxy, or C1-C6 haloalkoxy;
• R2a and R6a are each independently H, halo, C1-C6 alkyl, or C1-C6 haloalkyl;
• R4b1 and R4b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl;
• R5b1 and R5b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl;
• X4c is N or C—R4c;
• X5c is N or C—R5c;
• X6c is N or C—R6c;
• R2c is H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L1-L2-(C3-C6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo;
• L1 is a bond or O;
• L2 is a bond or C1-C6 alkylene;
• R4c is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
• R5c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl;
• and
• R6c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl;
• (i) X5a is C—R5a;
• R5a is halo, CH2OH, C1-C6 alkyl, or C1-C6 haloalkyl;
• X3c is C—R3c;
• and
• (a) R3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl;
• or
• (b) R2c and R3c, together with the carbon atoms to which they are attached, form a ring of formula:
• wherein
• Z1 and Z2 are each independently O or CH2;
• and
• each R is independently H or halo;
• or
• (ii) X5a is N, N+—O−, or C—R5a;
• R5a is H;
• and
• X3c is N,
• provided that no more than two of X2a X3a X5a, and X6a are N or N+—O−;
• and
• provided that no more than one of X3c, X4c, X5c, and X6c is N.