Diaryl piperidine compounds as calcium channel blockers

A method to treat a condition modulated by calcium ion channel activity, which method comprises administering to a subject in need of such treatment an amount of the compound of formula (1) effective to ameliorate said condition, wherein said compound is of the formula:

• or a pharmaceutically acceptable salt or conjugate thereof, wherein
• X is an optionally substituted alkylene (1-6C), alkenylene (2-6C), alkynylene (2-6C), heteroalkylene (2-6C), heteroalkenylene (2-6C), or heteroalkynylene (2-6C);
• Y is CR′2, O, S(O)q or NR′ wherein q is 0-2 and each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C) heteroalkenyl (2-6), heteroalkynyl (2-6C), heteroaryl (5-12C), aryl (6-10C), C5-C12-heteroaryl-C1-C6-alkyl, and C6-C12-aryl-C1-C6-alkyl;
• each Ar is independently an optionally substituted aromatic or heteroaromatic ring and wherein the two Ar groups may be linked together to form an optionally substituted fluorenyl;
• each R1, R2 and R3 is independently ═O, ═NOR′, halo, CN, OR′, SR′, SOR′, SO2R′, NR′2, NR′(CO)R′, or NR′SO2R′, wherein each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C) heteroalkenyl (2-6), heteroalkynyl (2-6C), heteroaryl (5-12C), aryl (6-10C), C5-C12-heteroaryl-C1-C6-alkyl, and C6-C12-aryl-C1-C6-alkyl;
• or each R1, R2 and R3 may independently be an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C), aryl (6-10C), heteroaryl (5-12C), O-aryl (6-10C), O-heteroaryl (5-12C), C5-C12-heteroaryl-C1-C6-alkyl, and C6-C12-aryl-C1-C6-alkyl;
• a is 0-5, b is 0-1 and c is 0-4;
• and
• wherein the optional substituents on each Ar, X, R′, R1, R2 and R3 are independently selected from halo, CN, NO2, CF3, OCF3, 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 alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C) heteroalkenyl (2-6), heteroalkynyl (2-6C), heteroaryl (5-12C), aryl (6-10C), C5-C12-heteroaryl-C1-C6-alkyl, and C6-C12-aryl-C1-C6-alkyl;
• or the optional substituent may be an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C), aryl (6-10C), heteroaryl (5-12C), O-aryl (6-10C), O-heteroaryl (5-12C) and C6-C12-aryl-C1-C6-alkyl;
• and wherein the optional substituent on X may further be selected from ═O and ═NOR″.

A compound of the formula:

• or a pharmaceutically acceptable salt or conjugate thereof, wherein
• X is an optionally substituted alkylene (1-6C), alkenylene (2-6C), alkynylene (2-6C), heteroalkylene (2-6C), heteroalkenylene (2-6C), or heteroalkynylene (2-6C);
• Y is CR′2, O, S(O)q or NR′ wherein q is 0-2 and each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C) heteroalkenyl (2-6), heteroalkynyl (2-6C), heteroaryl (5-12C), aryl (6-10C), C5-C12-heteroaryl-C1-C6-alkyl, and C6-C12-aryl-C1-C6-alkyl;
• each Ar is independently an optionally substituted aromatic or heteroaromatic ring and wherein the two Ar groups may be linked together to form an optionally substituted fluorenyl;
• each R1, R2 and R3 is independently ═O, ═NOR′, halo, CN, OR′, SR′, SOR′, SO2R′, NR′2, NR′(CO)R′, or NR′SO2R′, wherein each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C) heteroalkenyl (2-6), heteroalkynyl (2-6C), heteroaryl (5-12C), aryl (6-10C), C5-C12-heteroaryl-C1-C6-alkyl, and C6-C12-aryl-C1-C6-alkyl;
• or each R1, R2 and R3 may independently be an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C), aryl (6-10C), heteroaryl (5-12C), O-aryl (6-10C), O-heteroaryl (5-12C), C5-C12-heteroaryl-C1-C6-alkyl, and C6-C12-aryl-C1-C6-alkyl;
• a is 0-5, b is 0-1 and c is 0-4;
• and
• wherein the optional substituents on each Ar, X, R′, R1, R2 and R3 are independently selected from halo, CN, NO2, CF3, OCF3, 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 alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C) heteroalkenyl (2-6), heteroalkynyl (2-6C), heteroaryl (5-12C), aryl (6-10C), C5-C12-heteroaryl-C1-C6-alkyl, and C6-C12-aryl-C1-C6-alkyl;
• or the optional substituent may be an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C), aryl (6-10C), heteroaryl (5-12C), O-aryl (6-10C), O-heteroaryl (5-12C) and C6-C12-aryl-C1-C6-alkyl;
• and wherein the optional substituent on X may further be selected from ═O and ═NOR″;
• with the proviso that if X is (CH2)2-4O, then at least one Ar is unsubstituted.

A library of compounds, which library comprises at least 10 compounds of formula (1):

• or a pharmaceutically acceptable salt or conjugate thereof, wherein
• X is an optionally substituted alkylene (1-6C), alkenylene (2-6C), alkynylene (2-6C), heteroalkylene (2-6C), heteroalkenylene (2-6C), or heteroalkynylene (2-6C);
• Y is CR′2, O, S(O)q or NR′ wherein q is 0-2 and each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C) heteroalkenyl (2-6), heteroalkynyl (2-6C), heteroaryl (5-12C), aryl (6-10C), C5-C12-heteroaryl-C1-C6-alkyl, and C6-C12-aryl-C1-C6-alkyl;
• each Ar is independently an optionally substituted aromatic or heteroaromatic ring and wherein the two Ar groups may be linked together to form an optionally substituted fluorenyl;
• each R1, R2 and R3 is independently ═O, ═NOR′, halo, CN, OR′, SR′, SOR′, SO2R′, NR′2, NR′(CO)R′, or NR′SO2R′, wherein each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C) heteroalkenyl (2-6), heteroalkynyl (2-6C), heteroaryl (5-12C), aryl (6-10C), C5-C12-heteroaryl-C1-C6-alkyl, and C6-C12-aryl-C1-C6-alkyl;
• or each R1, R2 and R3 may independently be an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C), aryl (6-10C), heteroaryl (5-12C), O-aryl (6-10C), O-heteroaryl (5-12C), C5-C12-heteroaryl-C1-C6-alkyl, and C6-C12-aryl-C1-C6-alkyl;
• a is 0-5, b is 0-1 and c is 0-4;
• and
• wherein the optional substituents on each Ar, X, R′, R1, R2 and R3 are independently selected from halo, CN, NO2, CF3, OCF3, 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 alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C) heteroalkenyl (2-6), heteroalkynyl (2-6C), heteroaryl (5-12C), aryl (6-10C), C5-C12-heteroaryl-C1-C6-alkyl, and C6-C12-aryl-C1-C6-alkyl;
• or the optional substituent may be an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C), aryl (6-10C), heteroaryl (5-12C), O-aryl (6-10C), O-heteroaryl (5-12C) and C6-C12-aryl-C1-C6-alkyl;
• and wherein the optional substituent on X may further be selected from ═O and ═NOR″;
• with the proviso that if X is (CH2)2-4O, then at least one Ar is unsubstituted.