FLUORESCENCE POLARIZATION hERG ASSAY

A fluorescent tracer compound of structural formula:

• or a pharmaceutically acceptable salt thereof, wherein:
• Ar is an aromatic ring selected from the group consisting of benzo, thieno, furo, and pyrido;
• R1 and R2 are independently selected from the group consisting of:
• 1) hydrogen,
• 2) C1-6 alkyl, either unsubstituted or substituted with
• a) —NR4R5, wherein R4 and R5 are independently hydrogen or C1-6 alkyl,
• b) —N(R5)COC1-6 alkyl,
• c) —NHSO2(C1-6 alkyl),
• d) —CONR6R7, wherein R6 and R7 are independently
• i) hydrogen,
• ii) C1-6 alkyl, or
• iii) R6 and R7 taken together with the nitrogen atom to which they are attached represent a 5- or 6-membered saturated heterocyclic ring, which may contain an additional heteroatom selected from N, S(O)n, or O, selected from the group consisting of pyrrolidine, morpholine, piperidine, piperazine, and N-methylpiperazine,
• e) —CO(C1-6 alkyl),
• f) —OH,
• g) —O(C1-6 alkyl),
• h) —O(C1-6 alkyl)-O-(C1-3 alkyl),
• i) —S(O)n(C1-6 alkyl),
• j) imidazole,
• k) 2-imidazolidinone,
• l) 2-pyrrolidinone,
• m) —NH—C(NHR5)═N—CN, or
• n) —NH—C(SR5)═N—CN,
• 3) —OH,
• 4) C1-3 alkoxy, either unsubstituted or substituted with C1-3 alkoxy,
• 5) —N(R5)SO2(C1-6 alkyl),
• 6) —N(R5)SO2(CH2)gCO2H, wherein g is 1-5,
• 7) —N(R5)SO2(CH2)gCO2C1-6 alkyl,
• 8) —NO2,
• 9) —N(R5)COC1-6 alkyl,
• 10) —N(R5)SO2—C6H4—R4,
• 11) —N(R5)CO—C6H4—R4,
• 12) —NR4R5,
• 13) halo,
• 14) —CO—C1-6 alkyl,
• 15) —CONR6R7,
• 16) —CN,
• 17) —CO2R5,
• 18) —C(R5)═N—OR8,
• 19) benzoyl, either unsubstituted or substituted with C1-6 alkyl, C1-6 alkoxy, halo, or hydroxy,
• 20) —N(R5)COO(C1-6 alkyl),
• 21) —N(R5)COO-phenyl, either unsubstituted or substituted with C1-6 alkyl, C1-6 alkoxy, hydroxy or halo,
• 22) —N(R5)CONR4R5,
• 23) —S(O)nC1-6 alkyl,
• 24) —S(O)n—C6H4—R4
• 25) —CF3,
• 26) phenyl, either unsubstituted or substituted with C1-6 alkyl, C1-6 alkoxy, halo or hydroxy,
• 27) imidazolyl,
• 28) —SO2NR6R7.
• 29) —N[S(O)2C1-6alkyl][(CH2)pCN], wherein p is 2-5,
• 30) —N(R5)—C(NR4R5)═N—CN, and
• 31) —N(R5)—C(SR5)═N—CN;
• the ring system comprising W, X, and Y is a 5-, 6-, or 7-membered ring system wherein W, X, and Y are independently —O—, C═O, —(CR4R5)n—, C═NOR8, CHOR9, —NR9—, CHNR10R11, —S(O)n—, ═CH—, ═N—, or a bond;
• wherein:
• R4 and R5 are as defined above,
• R8 is
• a) hydrogen, or
• b) C1-6 alkyl, unsubstituted or substituted with —COOR5;
• R9 is
• a) hydrogen,
• b) C1-6 alkyl,
• c) (CH2)n—C6H4—R2, wherein R12 is
• i) —NO2,
• ii) C1-3 alkyl,
• iii) —O—C1-3 alkyl,
• iv) halo,
• v) —CF3, or
• vi) hydrogen,
• d) —CO—C1-6 alkyl,
• e) —CO—C6H4—R1,
• f) —COO—C1-6 alkyl, or
• g) —CONR4R5;
• R10 and R11 are independently
• a) hydrogen,
• b) C1-6 alkyl, unsubstituted or substituted with —(CR4R5)n—(CR4R5)g—R13, wherein g is 1-5, and R13 is
• i) hydrogen,
• ii) —OH, or
• iii) —OC1-6 alkyl,
• c) —CO—C1-6 alkyl, unsubstituted or substituted with
• i) —OH,
• ii) —N(R4R5),
• iii) —OC1-6 alkyl, or
• iv) —CO2R5,
• d) —CO—C6H4—R13, or
• e) R10 and R11 taken together with the nitrogen atom to which they are attached represent a 5- or 6-membered saturated heterocyclic ring, unsubstituted or substituted with oxygen or hydroxy, which may contain an additional heteroatom selected from N, S(O), or O, selected from the group consisting of pyrrolidine, morpholine, piperidine, pyrrolidinone, piperidinone, piperazine and N-methylpiperazine;
• n is 0, 1, or 2;
• B is a 5- to 7-membered N-containing ring;
• L is —(CR4R5)m-Q-(CR4R5)q—NH—[CZ-(CR4R5)n-(D)w]z—, wherein
• R4 and R5 are as defined above,
• m and q are independently 1 to about 5,
• u is 0 to about 7,
• w is 0 or 1,
• z is 1 or 2,
• Q is a bond, —O—, C═O, CHOH, —NR5— or —S(O)n—,
• Z is ═O or ═S, and
• D is —O—, —S(O)n—, —NR5—, or —NR5SO2—;
• and
• R3 is a fluorescent dye.