Pyridylphenyl compounds for inflammation and immune-related uses

A method of inhibiting cytokine production in a cell, comprising administering to the cell a compound represented by structural formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• Y1 is a monocyclic optionally substituted aryl or a monocyclic optionally substituted heteroaryl, provided that Y1 is not a substituted isoxazolyl or a substituted 1H-pyrrolyl;
• L1 is a linker selected from the group consisting of —NHCH2—, —CH2NH—, —NR—C(O)—, —OC(O)—, —C(O)O—, —C(S)—, —NR—C(S)—, and —C(S)—NR—;
• one of X1 or X2 is CH or CZ and the other is N;
• each Z is independently selected from the group consisting of a lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower alkyl sulfanyl, —S(O)p-alkyl, —C(O)NRR, —(CH2)kNRR, —(CH2)kOR, —(CH2)kSR, cyano, nitro, and lower haloalkoxy;
• R, for each occurrence is independently selected from —H or an alkyl;
• R3 is H, an alkyl, a haloalkyl, a halo, a haloalkoxy, —OR5, —SR5, or —NR6R7;
• R4 is oxazol-2-yl, oxazol-5-yl, thiazol-2-yl, thiazol-5-yl, [1,3,4]oxadiazol-2-yl, pyridin-3-yl, or pyridin-2-yl;
• R5, for each occurrence, is independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
• R6 and R7, for each occurrence are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
• or R6 and R7 taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
• q, for each occurrence, is independently, an integer from 1 to 3;
• k is for each occurrence, is independently, an integer from 1 to 4;
• n is zero, 1 or 2;
• and
• p, for each occurrence, is independently 1 or 2.

A method of modulating an ion channel in a cell, wherein the ion channel is involved in immune cell activation, comprising administering to the cell a compound represented by structural formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• Y1 is a monocyclic optionally substituted aryl or a monocyclic optionally substituted heteroaryl, provided that Y1 is not a substituted isoxazolyl or a substituted 1H-pyrrolyl;
• L1 is a linker selected from the group consisting of —NHCH2—, —CH2NH—, —NR—C(O)—, —OC(O)—, —C(O)O—, —C(S)—, —NR—C(S)—, and —C(S)—NR—;
• one of X1 or X2 is CH or CZ and the other is N;
• each Z is independently selected from the group consisting of a lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower alkyl sulfanyl, —S(O)p-alkyl, —C(O)NRR, —(CH2)kNRR, —(CH2)kOR, —(CH2)kSR, cyano, nitro, and lower haloalkoxy;
• R, for each occurrence is independently selected from —H or an alkyl;
• R3 is H, an alkyl, a haloalkyl, a halo, a haloalkoxy, —OR5, —SR5, or —NR6R7;
• R4 is oxazol-2-yl, oxazol-5-yl, thiazol-2-yl, thiazol-5-yl, [1,3,4]oxadiazol-2-yl, pyridin-3-yl, or pyridin-2-yl;
• R5, for each occurrence, is independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
• R6 and R7, for each occurrence are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
• or R6 and R7 taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
• q, for each occurrence, is independently, an integer from 1 to 3;
• k is for each occurrence, is independently, an integer from 1 to 4;
• n is zero, 1 or 2;
• and
• p, for each occurrence, is independently 1 or 2.

A method of inhibiting T-cell and/or B-cell proliferation in response to an antigen, comprising administering to the cell a compound represented by structural formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• Y1 is a monocyclic optionally substituted aryl or a monocyclic optionally substituted heteroaryl, provided that Y1 is not a substituted isoxazolyl or a substituted 1H-pyrrolyl;
• L1 is a linker selected from the group consisting of —NHCH2—, —CH2NH—, —NR—C(O)—, —OC(O)—, —C(O)O—, —C(S)—, —NR—C(S)—, and —C(S)—NR—;
• one of X1 or X2 is CH or CZ and the other is N;
• each Z is independently selected from the group consisting of a lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower alkyl sulfanyl, —S(O)p-alkyl, —C(O)NRR, —(CH2)kNRR, —(CH2)kOR, —(CH2)kSR, cyano, nitro, and lower haloalkoxy;
• R, for each occurrence is independently selected from —H or an alkyl;
• R3 is H, an alkyl, a haloalkyl, a halo, a haloalkoxy, —OR5, —SR5, or —NR6R7;
• R4 is oxazol-2-yl, oxazol-5-yl, thiazol-2-yl, thiazol-5-yl, [1,3,4]oxadiazol-2-yl, pyridin-3-yl, or pyridin-2-yl;
• R5, for each occurrence, is independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
• R6 and R7, for each occurrence are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
• or R6 and R7 taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
• q, for each occurrence, is independently, an integer from 1 to 3;
• k is for each occurrence, is independently, an integer from 1 to 4;
• n is zero, 1 or 2;
• and
• p, for each occurrence, is independently 1 or 2.