Atropisomers of 3-aryl-4(3H)-quinazolinones and their use as AMPA-receptor antagonists

An atropisomer of the formula

• wherein R2 is a phenyl group of the formula Ph2 or a five or six membered heterocycle, wherein said 6-membered heterocycle has the formula
• wherein “N” is nitrogen;
• wherein said ring positions “K”, “L” and “M” may be independently selected from carbon or nitrogen with the proviso that i) only one of “K”, “L” and “M” can be nitrogen and ii) when “K”, “L” or “M” is nitrogen, then its respective R15, R16 or R17 is absent;
• wherein said five membered heterocycle has the formula
• wherein said “T” is —CH—, N, NH, or O;
• wherein said ring positions “P” and “Q” may be independently selected from carbon, nitrogen, oxygen or sulfur;
• with the proviso that (i) only one of “P,” “Q” or “T” can be oxygen, NH or sulfur;
• (ii) at least one of “P”, “Q” or “T” must be a heteroatom;
• (iii) when “P” or “Q” is oxygen or sulphur then its respective R15 or R16 is absent;
• (iv) and when Q is sulfur, then T can not be carbon;
• wherein said Ph2 is a group of the formula
• R3 is hydrogen, halo, —CN, —NO2, CF3, (C1-C6)alkyl or (C1-C6)alkoxy;
• R5 is halo, CF3, or (C1-C6)alkylthiol;
• R6 is hydrogen or halo;
• R7 is hydrogen or halo;
• R8 is hydrogen or halo;
• R9 is hydrogen, halo, CF3, (C1-C6)alkyl optionally substituted with one to three halogen atoms, (C1-C6)alkoxy optionally substituted with one to three halogen atoms, (C1-C6)alkylthiol, amino-(CH2)s—, (C1-C6)alkyl-NH—(CH2)s—, di(C1-C6)alkyl-N—(CH2)s—, (C3-C7)cycloalkyl-NH—(CH2)s—, H2N—(C═O)—(CH2)s—, (C1-C6)alkyl-HN—(C═O)—(CH2)s—, di(C1-C6)alkyl-N—(C═O)—(CH2)s—, (C3-C7)cycloalkyl-NH—(C═O)—(CH2)s—, R13O—(CH2)s—, R13O—(C═O)—(CH2)s—, H(O═C)—NH—(CH2)s—, (C1-C6)alkyl-(O═C)—NH—(CH2)s—,
• H—(C═O)—(CH2)s—, (C1-C6)alkyl—(C═O)—, hydroxy, hydroxy-(C1-C6)alkyl-, (C1-C6)alkyl-O—(C1-C6)alkyl-, and —CN;
• R10 is hydrogen or halo;
• R11 and R14 selected, independently, from, are hydrogen, halo, CF3, (C1-C6)alkyl optionally substituted with one to three halogen atoms, (C1-C6)alkoxy optionally substituted with one to three halogen atoms, (C1-C6)alkylthiol, amino-(CH2)p—, (C1-C6)alkyl-NH—(CH2)p—, di(C1-C6)alkyl-N—(CH2)p—, (C3-C7)cycloalkyl-NH—(CH2)p—, amino-(C1-C6)alkyl-NH—(CH2)p—, (C1-C6)alkyl-NH—(C1-C6)alkyl-NH—(CH2)p—, di(C1-C6)alkyl-N—(C1-C6)alkyl-NH—(CH2)p—,
• H2N—(C═O)—(CH2)p—, (C1-C6)alkyl-HN—(C═O)—(CH2)p—, di(C1-C6)alkyl-N—(C═O)—(CH2)p, (C3-C7)cycloalkyl-NH—(C═O)—(CH2)p—, R13O—(CH2)p—, R13O—(C═O)—(CH2)p—, H(O═C)—O—, H(O═C)—O—(C1-C6)alkyl-, H(O═C)—NH—(CH2)p—, (C1-C6)alkyl-(O═C)—NH—(CH2)p—, —CHO, H—(C═O)—(CH2)p—, (C1-C6)alkyl-(C═O)—(CHp—,
• (C1-C6)alkyl-(C═O)—O—(CH2)p—, amino-(C1-C6)alkyl-(C═O)—O—(CH2)p—, (C1-C6)alkyl-NH—(C1-C6)alkyl-(C═O)—O—(CH2)p—, di(C1-C6)alkyl-N—(C1-C6)alkyl-(C═O)—O—(CH2)p—, amino-(C1-C6)alkyl-O—(C═O)—(CH2)p—, (C1-C6)alkyl-NH—(C1-C6)alkyl-O—(C═O)—(CH2)p—, di(C1-C6)alkyl-N—(C1-C6)alkyl-O—(C═O)—O—(CH2)p—, hydroxy, hydroxy-(C1-C6)alkyl-, hydroxy-(C1-C6)alkyl-NH—(CH2)p—, (C1-C6)alkyl-O—(C1-C6)alkyl-, —CN, piperidine-(CH2)p—, pyrrolidine-(CH2)p—, or 3-pyrroline-(CH2)p—, wherein said piperidine, pyrrolidine and 3-pyrroline of said piperidine-(CH2)p—, pyrrolidine-(CH2)p— and 3-pyrroline-(CH2)p— moieties may optionally be substituted on any of the ring carbon atoms capable of supporting an additional bond, preferably zero to two substituents, with a substituent independently selected from halo, CF3, (C1-C6)alkyl optionally substituted with one to three halogen atoms, (C1-C6)alkoxy optionally substituted with one to three halogen atoms, (C1-C6)alkylthiol, amino-(CH2)p—, (C1-C6)alkyl-NH—(CH2)p—, di(C1-C6)alkyl-N—(CH2)p—, (C3-C7)cycloalkyl-NH—CH2)p—, amino-(C1≠C6)alkyl-NH—(CH2)p—, (C1-C6)alkyl-NH—(C1-C6)alkyl-NH—(CH2)p—, di(C1-C6)alkyl-N—(C1-C6)alkyl-NH—(CH2)p—, (C1-C6)alkyl-O—(C1-C6)alkyl-,
• H2N—(C═O)—(CH2)p—, (C1-C6)alkyl-HN—(C═O)—(CH2)p—, di(C1-C6)alkyl-N—(C═O)—(CH2)p, (C3-C7)cycloalkyl-NH—(C═O)—(CH2)p—, R13O—(C═O)—(CH2)p—, H(O═C)—O—, H(O═C)—O—(C1≠C6)alkyl-, H(O═C)—NH—(CH2)p—, (C1≠C6)alkyl-(O═C)—NH—(CH2)p—, —CHO, H—(C═O)—(CH2)p—, (C1-C6)alkyl-(C═O)—,
• (C1-C6)alkyl-(C═O)—O—NH—(CH2)p—, amino-(C1-C6)alkyl-(C═O)—O—(CH2)p—, (C1-C6)alkyl-NH—(C1-C6)alk-yl-(C═O)—O—(CH2)p—, di(C1≠C6)alkyl-N—(C1-C6)alkyl-(C═O)—O—(CH2)p—, hydroxy, hydroxy-(C1-C6)alkyl-, hydroxy-(C1-C6)alkyl-NH—(CH2)p—, and —CN;
• R12 is hydrogen, —CN or halo;
• R13 is hydrogen, (C1-C6)alkyl, (C1-C6)alkyl-(C═O)—, (C1-C6)alkyl-O—(C═O)—, (C1-C6)alkyl-NH(C1-C6)alkyl, di(C1-C6)-alkyl-N—(C1-C6)alkyl-, (C1-C6)alkyl-NH—(C═O)—, or di(C1-C6)alkyl-N—(C═O)—;
• R15 is hydrogen, —CN, (C1≠C6)alkyl, halo, CF3, —CHO or (C1-C6)alkoxy;
• R16 is hydrogen, —CN, (C1-C6)alkyl, halo, CF3, —CHO or (C1-C6)alkoxy;
• R17 is hydrogen, —CN, (C1-C6)alkyl, amino-(C1-C6)alkyl-, (C1-C6)alkyl-NH—(C1-C6)alkyl-, di(C1-C6)alkyl-N—(C1-C6)alkyl-, halo, CF3, —CHO or (C1-C6)alkoxy;
• n is an integer from zero to 3;
• each p is independently an integer from zero to 4;
• s is an integer from zero to 4;
• wherein the dashed bond represented an optional double bond;
• and the pharmaceutically acceptable salts of such compounds.