Bicyclic pyrimidine derivatives as calcium channel blockers

A pharmaceutical composition comprising a compound of the formula:

• or a pharmaceutically acceptable salt or conjugate thereof in admixture with a pharmaceutically acceptable excipient, wherein
• each R1 and R2 is, independently, H, or an optionally substituted C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 heteroalkyl, C2-6 heteroalkenyl, C2-6 heteroalkynyl, C6-10 aryl, C5-12 heteroaryl, or C6-12 aryl-C1-6 alkyl;
• or R1 and R2 together form an optionally substituted 3-8 membered heterocyclic ring or 5-12 membered heteroaromatic ring;
• each R3 and R4 is, independently, H, halo or an optionally substituted C1-3 alkyl or C1-3 heteroalkyl;
• X is an optionally substituted C1-3 alkylene or C1-3 heteroalkylene;
• Y is Ar or N(R5)(R6), wherein Ar is an optionally substituted C6-10 aryl or C5-12 heteroaryl and R5 and R6 are independently, H, or an optionally substituted C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 heteroalkyl, C2-6 heteroalkenyl, C2-6 heteroalkynyl, C6-10 aryl, C5-12 heteroaryl, or C6-12 aryl-C1-6 alkyl;
• or R5 and R6 together form an optionally substituted 3-8 membered heterocyclic ring or 5-12 membered heteroaromatic ring;
• wherein the optional substituents on each X, Ar, R1, R2, R3, R4 and R5 is, independently, selected from the group consisting of 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 the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 heteroalkyl, C2-6 heteroalkenyl, and C2-6 heteroalkynyl;
• or the optional substituents may be one or more optionally substituted groups selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 heteroalkyl, C2-6 heteroalkenyl, and C2-6 heteroalkynyl;
• and wherein the optional substituent on X, R1, R2, R5 and R6 may further be selected from ═O or ═NOR′;
• and wherein optional substituents on a heterocyclic ring formed with R1 and R2 or R5 and R6 may independently be selected from the group consisting of ═O, ═NOR′, 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 the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 heteroalkyl, C2-6 heteroalkenyl, and C2-6 heteroalkynyl;
• or the optional substituents may be one or more optionally substituted groups selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 heteroalkyl, C2-6 heteroalkenyl, and C2-6 heteroalkynyl, C6-10 aryl, C5-12 heteroaryl, and C6-12 aryl-C1-6 alkyl;
• with the following two provisos that for compounds of formula (I):
• when Y is N(R5)(R6), a carbon atom in X or Y that is adjacent to the N in Y is substituted by ═O;
• and when Y is Ar, then neither R1 nor R2 are arylalkyl.