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 formula (I):

• or a pharmaceutically acceptable salt wherein:
• X is an optionally substituted benzoimidazolyl, an optionally substituted 5,6,7,8-tetrahydroindolizinyl, an optionally substituted imidazo[4,5-a]pyridyl, an optionally substituted imidazo[1,2-a]pyridyl, an optionally substituted imidazo[4,5-b]pyridyl, or an optionally substituted imidazo[4,5-c]pyridyl;
• Y is an unsubstituted alkyl, an optionally substituted alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl;
• A is —O—, —S(O)p—, —NH—, —NZ—, —CH═CH—, —CZ═CH—, —CH═CZ—, —CZ═CZ—, —N═CH—, —N═CZ—, —CH═N—, —CZ═N—, or an N-oxide of —N═CH—, —N═CZ—, —CH═N—, or —CZ═N—;
• wherein when X is an optionally substituted benzoimidazolyl, A is not —CH═CH—, —CZ═CH—, —CH═CZ—, or —CZ═CZ—;
• Z, for each occurrence, is independently selected from the group consisting of 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, an optionally substituted heteraralkyl, a haloalkyl, —C(O)NR1R2, —NR4C(O)R5, halo, —OR4, cyano, nitro, haloalkoxy, —C(O)R4, —NR1R2, —C(O)OR4, —OC(O)R4, —NR4C(O)NR1R2, —OC(O)NR1R2, —NR4C(O)OR5, —S(O)pR4, or —S(O)hNR1R2;
• L is a linker selected from the group consisting of an optionally substituted lower alkyl, and optionally substituted lower alkenyl, —NRCR4R5—, —C(O)—, —OC(O)—, —C(O)O—, —NR—C(O)—, —C(O)—NR—, —NR—C(O)—NR—, —C(S)—, —NR—S(O)h—, —S(O)h—NR—, —NR—C(═NR)—, —NR—C(═NR)—NR—, —NR—C(═N—CN)—NR—, —NR—C(═N—NO2)—NR—, —NR—C(S)—, —C(S)—NR—, or —NR—C(S)—NR—;
• R, for each occurrence, is independently selected from —H, an alkyl, acetyl, alkoxycarbonyl, or aralkoxycarbonyl;
• R1 and R2, 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 R1 and R2 taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl;
• R4 and R5 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;
• h is 1 or 2;
• n is 0 or an integer from 1 to 4;
• and
• p, for each occurrence, is, independently, 0, 1, or 2.

A method of modulating an ion channel by activating a TRPM4 ion channel, inhibiting a Kv1.3 ion channel, or inhibiting a CRAC ion channel in a cell, comprising administering to the cell a compound represented by formula (I):

• or a pharmaceutically acceptable salt thereof wherein:
• X is an optionally substituted benzoimidazolyl, an optionally substituted 5,6,7,8-tetrahydroindolizinyl, an optionally substituted imidazo[4,5-a]pyridyl, an optionally substituted imidazo[1,2-a]pyridyl, an optionally substituted imidazo[4,5-b]pyridyl, or an optionally substituted imidazo[4,5-c]pyridyl;
• Y is an unsubstituted alkyl, an optionally substituted alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl;
• A is —O—, —S(O)p—, —NH—, —NZ—, —CH═CH—, —CZ═CH—, —CH═CZ—, —CZ═CZ—, —N═CH—, —N═CZ—, —CH═N—, —CZ═N—, or an N-oxide of —N═CH—, —N═CZ—, —CH═N—, or —CZ═N—;
• wherein when X is an optionally substituted benzoimidazolyl, A is not —CH═CH—, —CZ═CH—, —CH═CZ—, or —CZ═CZ—;
• Z, for each occurrence, is independently selected from the group consisting of 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, an optionally substituted heteraralkyl, a haloalkyl, —C(O)NR1R2, —NR4C(O)R5, halo, —OR4, cyano, nitro, haloalkoxy, —C(O)R4, —NR1R2, —C(O)OR4, —OC(O)R4, —NR4C(O)NR1R2, —OC(O)NR1R2, —NR4C(O)OR5, —S(O)pR4, or —S(O)hNR1R2;
• L is a linker selected from the group consisting of an optionally substituted lower alkyl, and optionally substituted lower alkenyl, —NRCR4R5—, —C(O)—, —OC(O)—, —C(O)O—, —NR—C(O)—, —C(O)—NR—, —NR—C(O)—NR—, —C(S)—, —NR—S(O)h—, —S(O)h—NR—, —NR—C(═NR)—, —NR—C(═NR)—NR—, —NR—C(═N—CN)—NR—, —NR—C(═N—NO2)—NR—, —NR—C(S)—, —C(S)—NR—, or —NR—C(S)—NR—;
• R, for each occurrence, is independently selected from —H, an alkyl, acetyl, alkoxycarbonyl, or aralkoxycarbonyl;
• R1 and R2, 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 R1 and R2 taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl;
• R4 and R5 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;
• h is 1 or 2;
• n is 0 or an integer from 1 to 4;
• and
• p, for each occurrence, is, independently, 0, 1, or 2.

A method of inhibiting immune cell proliferation in response to an antigen, comprising administering to the cell a compound represented by formula (I):

• or a pharmaceutically acceptable salt thereof wherein:
• X is an optionally substituted benzoimidazolyl, an optionally substituted 5,6,7,8-tetrahydroindolizinyl, an optionally substituted imidazo[4,5-a]pyridyl, an optionally substituted imidazo[1,2-a]pyridyl, an optionally substituted imidazo[4,5-b]pyridyl, or an optionally substituted imidazo[4,5-c]pyridyl;
• Y is an unsubstituted alkyl, an optionally substituted alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl;
• A is —O—, —S(O)p—, —NH—, —NZ—, —CH═CH—, —CZ═CH—, —CH═CZ—, —CZ═CZ—, —N═CH—, —N═CZ—, —CH═N—, —CZ═N—, or an N-oxide of —N═CH—, —N═CZ—, —CH═N—, or —CZ═N—;
• wherein when X is an optionally substituted benzoimidazolyl, A is not —CH═CH—, —CZ═CH—, —CH═CZ—, or —CZ═CZ—;
• Z, for each occurrence, is independently selected from the group consisting of 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, an optionally substituted heteraralkyl, a haloalkyl, —C(O)NR1R2, —NR4C(O)R5, halo, —OR4, cyano, nitro, haloalkoxy, —C(O)R4, —NR1R2, —C(O)OR4, —OC(O)R4, —NR4C(O)NR1R2, —OC(O)NR1R2, —NR4C(O)OR5, —S(O)pR4, or —S(O)hNR1R2;
• L is a linker selected from the group consisting of an optionally substituted lower alkyl, and optionally substituted lower alkenyl, —NRCR4R5—, —C(O)—, —OC(O)—, —C(O)O—, —NR—C(O)—, —C(O)—NR—, —NR—C(O)—NR—, —C(S)—, —NR—S(O)h—, —S(O)h—NR—, —NR—C(═NR)—, —NR—C(═NR)—NR—, —NR—C(═N—CN)—NR—, —NR—C(═N—NO2)—NR—, —NR—C(S)—, —C(S)—NR—, or —NR—C(S)—NR—;
• R, for each occurrence, is independently selected from —H, an alkyl, acetyl, alkoxycarbonyl, or aralkoxycarbonyl;
• R1 and R2, 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 R1 and R2 taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl;
• R4 and R5 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;
• h is 1 or 2;
• n is 0 or an integer from 1 to 4;
• and
• p, for each occurrence, is, independently, 0, 1, or 2.

A method for treating an inflammatory condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound represented by formula (I):

• or a pharmaceutically acceptable salt thereof wherein:
• X is an optionally substituted benzoimidazolyl, an optionally substituted 5,6,7,8-tetrahydroindolizinyl, an optionally substituted imidazo[4,5-a]pyridyl, an optionally substituted imidazo[1,2-a]pyridyl, an optionally substituted imidazo[4,5-b]pyridyl, or an optionally substituted imidazo[4,5-c]pyridyl;
• Y is an unsubstituted alkyl, an optionally substituted alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl;
• A is —O—, —S(O)p—, —NH—, —NZ—, —CH═CH—, —CZ═CH—, —CH═CZ—, —CZ═CZ—, —N═CH—, —N═CZ—, —CH═N—, —CZ═N—, or an N-oxide of —N═CH—, —N═CZ—, —CH═N—, or —CZ═N—;
• wherein when X is an optionally substituted benzoimidazolyl, A is not —CH═CH—, —CZ═CH—, —CH═CZ—, or —CZ═CZ—;
• Z, for each occurrence, is independently selected from the group consisting of 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, an optionally substituted heteraralkyl, a haloalkyl, —C(O)NR1R2, —NR4C(O)R5, halo, —OR4, cyano, nitro, haloalkoxy, —C(O)R4, —NR1R2, —C(O)OR4, —OC(O)R4, —NR4C(O)NR1R2, —OC(O)NR1R2, —NR4C(O)OR5, —S(O)pR4, or —S(O)hNR1R2;
• L is a linker selected from the group consisting of an optionally substituted lower alkyl, and optionally substituted lower alkenyl, —NRCR4R5—, —C(O)—, —OC(O)—, —C(O)O—, —NR—C(O)—, —C(O)—NR—, —NR—C(O)—NR—, —C(S)—, —NR—S(O)h—, —S(O)h—NR—, —NR—C(═NR)—, —NR—C(═NR)—NR—, —NR—C(═N—CN)—NR—, —NR—C(═N—NO2)—NR—, —NR—C(S)—, —C(S)—NR—, or —NR—C(S)—NR—;
• R, for each occurrence, is independently selected from —H, an alkyl, acetyl, alkoxycarbonyl, or aralkoxycarbonyl;
• R1 and R2, 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 R1 and R2 taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl;
• R4 and R5 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;
• h is 1 or 2;
• n is 0 or an integer from 1 to 4;
• and
• p, for each occurrence, is, independently, 0, 1, or 2.