Patent EA-001961-B1 (EA)
Title: Atropisomers of 3-heteroaryl-4(3h)-quinazolinones for the treatment of neurodegenerative and cns-trauma related conditions
Inventor: CHENARD BERTRAND
IPC: C07D401/14
Filed: 1998-02-06
Abstract: 1. An atropisomer of the formula   wherein each of "A, B and D" is nitrogen or -CH-, with the proviso that only one of "A", "B" and "D" can be nitrogen; wherein n is an integer from one to four and wherein each R<5> is a substituent on any carbon atom of the "A, B, D" ring capable of supporting an additional bond, with the proviso that one R<5> must be attached to a carbon atom ortho to the asterisked carbon of the ring; wherein each R<5> may be independently selected from the group consisting of (C1-C6)alkyl, halogen, trifluoromethyl, amino-(CH2)m-, (C1-C6)alkylamino-(CH2)m-, di(C1-C6)alkylamino-(CH2)m-, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl-, (C1-C6)alkyl-O-(C1-C6)alkyl-, -CN, hydroxy-(CH2)m-, (C1-C6)alkyl-(O=C)-O-(C1-C6)alkyl-, (C1-C6)alkyl-O-(C=O)-O-(C1-C6)alkyl, (C1-C6)alkyl-(O=C)-O-, H-(C=O)-(CH2)m-, (C1-C6)alkyl-(C=O)-(CH2)m-, HO-(C=O)-, (C1-C6)alkyl-O-(C=O)-(CH2)m-, NH2-(C=O)-(CH2)m-, (C1-C6)-alkyl-NH-(C=O)-(CH2)m-, and di(C1-C6)alkyl-N-(C=O)-(CH2)m-; and wherein m is an integer from zero to four; R<2> 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 (atoms) "K", "L" and "M" may be independently selected from carbon and 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 substituent R<15>, R<16> or R<17> is absent; wherein said five membered heterocycle has the formula   wherein said "T" is -CH-, N, NH, O or S; wherein said ring positions "P" and "Q" may be independently selected from carbon, nitrogen, oxygen and sulfur; with the proviso that only one of "P," "Q" or "T" can be oxygen or sulfur and at least one of "P", "Q" or "T" must be a heteroatom; wherein said Ph<2> is a group of the formula   R<3> is hydrogen, halo, -CN, -NO2, CF3, (C1-C6)alkyl or (C1-C6)alkoxy; R<9> 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-C6alkyl)-N-(C=O)-(CH2)s-, (C3-C7)cycloalkyl-NH-(C=O)-(CH2)s-, R<13>O-(CH2)s-, R<13>O-(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-, or -CN; R<10> is hydrogen or halo; R<11> and R<14> are selected, independently, from 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-HN-(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-, R<13>O-(CH2)p-, R<13>O-(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)-(CH2)p-,    , (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)-(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-, and 3-pyrroline-(CH2)p-, wherein said piperidine, pyrrolidine and 3-pyrroline moieties of said piperidine-(CH2)p-, pyrrolidine-(CH2)p- and 3-pyrroline-(CH2)p- groups 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-, di(C1-C6)alkyl-N-(C1-C6)alkyl-N-(CH2)p-,                                                |                                              (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-, R<13>O-(CH2)p-, R<13>O-(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-   (C1-C6)alkyl-(C=O)-O-NH-(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-, hydroxy, hydroxy-(C1-C6)alkyl-, hydroxy-(C1-C6)alkyl-NH-(CH2)p- and -CN; R<12> is hydrogen, -CN or halo; R<13> 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)-; R<15> is hydrogen, -CN, (C1-C6)alkyl, halo, CF3, -CHO or (C1-C6)alkoxy; R<16> is hydrogen, -CN, (C1-C6)alkyl, halo, CF3, -CHO or (C1-C6)alkoxy; R<17> 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; 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. 2. A compound according to Claim 1 wherein R<3> is hydrogen, halo or (C1-C6)alkyl. 3. A compound according to Claim 1 wherein "B" is nitrogen, "A" and "D" are carbon and R<5> is hydrogen, halo, -CN, CF3, or (C1-C6)alkyl. 4. A compound according to Claim 1 wherein R<5> is chloro or methyl. 5. A compound according to Claim 3 wherein n is one and R<5> is a substituent ortho to the asterisked carbon. 6. A compound according to Claim 1 wherein R<2> is Ph<2> and R<9> is fluoro, chloro, -CN or hydroxy; or R<10> is -CHO, chloro, fluoro, methyl, (C1-C6)alkyl-NH-(CH2)p-, di(C1-C6)alkyl-N-(CH2)p-, or cyano. 7. A compound according to Claim 2 wherein R<2> is Ph<2> and R<9> is fluoro, chloro, -CN or hydroxy; or R<10> is -CHO, chloro, fluoro, methyl, (C1-C6)alkyl-NH-(CH2)p-, di(C1-C6)alkyl-N-(CH2)p-, or cyano. 8. A compound according to Claim 1 wherein R<2> is heteroaryl and said heteroaryl is either an optionally substituted six-membered heterocycle wherein "K", "L" and "M" are carbon, or "K" and "L" are carbon and "M" is nitrogen, or said heteroaryl is an optionally substituted five membered heterocycle wherein "T" is nitrogen, "P" is sulfur and "Q" is carbon, or "T" is nitrogen or sulfur, "Q" is nitrogen or sulfur and "P" is carbon or "T" is oxygen and "P" and "Q" are each carbon. 9. A compound according to Claim 2 wherein R<2> is heteroaryl and said heteroaryl is either an optionally substituted six-membered heterocycle wherein "K", "L" and "M" are carbon, or "K" and "L" are carbon and "M" is nitrogen, or said heteroaryl is an optionally substituted five membered heterocycle wherein "T" is nitrogen, "P" is sulfur and "Q" is carbon, or "T" is nitrogen or sulfur, "Q" is nitrogen or sulfur and "P" is carbon or "T" is oxygen and "P" and "Q" are each carbon. 10. A compound according to Claim 3 wherein R<2> is heteroaryl and said heteroaryl is either an optionally substituted six-membered heterocycle wherein "K", "L" and "M" are carbon, or "K" and "L" are carbon and "M" is nitrogen, or said heteroaryl is an optionally substituted five membered heterocycle wherein "T" is nitrogen, "P" is sulfur and "Q" is carbon, or "T" is nitrogen or sulfur, "Q" is nitrogen or sulfur and "P" is carbon or "T" is oxygen and "P" and "Q" are each carbon. 11. A compound according to Claim 1 wherein R<2> is an optionally substituted six-membered heterocycle wherein "K", "L" and "M" are carbon; R<14> is hydrogen, -CHO, chloro, fluoro, methyl, (C1-C6)alkyl-NH-(CH2)p-, di(C1-C6)alkyl-N-(CH2)p-, or cyano; R<17> is hydrogen, -CHO, chloro, fluoro, methyl, (C1-C6)alkyl-NH-(C1-C6)alkyl, di(C1-C6)alkyl-N-(C1-C6)alkyl, or cyano; or R<15> or R<16> are independently hydrogen, -CHO, chloro, fluoro, methyl, pyrrolidine-(CH2)p- or cyano. 12. A compound according to Claim 1 wherein R<2> is an optionally substituted six-membered heterocycle wherein "K", "L" and "M" are carbon; and R<14> is hydrogen, -CHO, methyl, (C1-C6)alkyl-NH-(CH2)p-, di(C1-C6)alkyl-N-(CH2)p-, pyrrolidine-(CH2)p- or cyano. 13. A compound according to Claim 1 wherein R<2> is an optionally substituted five-membered heterocycle wherein "T" is nitrogen, "P" is sulfur and "Q" is carbon; and R<14>, R<15> or R<16> are each independently hydrogen, chloro, fluoro, methyl or cyano. 14. A compound according to Claim 1 wherein R<2> is an optionally substituted five-membered heterocycle wherein "T" is nitrogen or sulfur, "Q" is sulfur or nitrogen and "P" is carbon; and R<14> or R<15> are independently hydrogen, chloro, fluoro, methyl or cyano. 15. A compound according to Claim 1 wherein said compound is selected from the group consisting of: (S)-6-fluoro-2-[2-(2-fluorophenyl)vinyl]-3-(2-methylpyridin-3-yl)-3H-quinazolin-4-one; (S)-2-{2-[6-fluoro-3-(2-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]vinyl}benzonitrile; (S)-2-{2-[6-fluoro-3-(2-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]vinyl}benzonitrile; (S)-2-{2-[3-(2-chloropyridin-3-yl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]vinyl}benzonitrile; (S)-2-{2-[6-fluoro-3-(2-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]vinyl}-4-methylbenzonitrile; (S)-2-[