Patent EA-001991-B1 (EA)
Title: 4,4-disubstituted -3,4-dihydro-2(1h)-quinazolinones useful as hiv reverse transcriptase inhibitots
Inventor: CORBETT JEFFREY W
IPC: C07D403/06
Filed: 1998-04-07
Abstract: 1. A compound of formula (I):   or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R<1> is C1-3-alkyl substituted with 1-7 halogen atoms; R<2> is selected from C1-5-alkyl substituted with 1-2 R<4>, C2-5-alkenyl substituted with 1-2 R<4>, and C2-5-alkynyl substituted with one R<4>; R<3> each is independently selected from C1-4-alkyl, OH, C1-4-alkoxy, F, Cl, Br, I, NR<5>R<5a>, NO2, CN, C(O)R<6>, NHC(O)R<7>, and NHC(O)NR<5>R<5a>; alternatively, if two R<3> substituents are present and are attached to adjacent carbons, then they may combine to form -OCH2O-; R<4> is selected from C3-5-cycloalkyl substituted with 0-2 R<3>, phenyl substituted with 0-5 R<3>, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-2 R<3>; R<5> and R<5>a are independently selected from H and C1-3-alkyl; R<6> is selected from H, OH, C1-4-alkyl, C1-4-alkoxy, and NR<5>R<5a>; R<7> is selected from C1-3-alkyl and C1-3-alkoxy; R<8> is selected from H, C3-5-cycloalkyl, and C1-3-alkyl; and, n is selected from 0, 1, 2, 3, and 4. 2. A compound according to Claim 1, wherein: R<1> is C1-3-alkyl substituted with 1-7 halogen; R<2> is selected from C1-5-alkyl substituted with one R<4>, C2-5-alkenyl substituted with one R<4>, and C2-5-alkynyl substituted with one R<4>; R<3> each is independently selected from C1-4-alkyl, OH, C1-4-alkoxy, F, Cl, Br, I, NR<5>R<5a>, NO2, CN, C(O)R<6>, NHC(O)R<7>, and NHC(O)NR<5>R<5a>; alternatively, if two R<3> substituents are present and are attached to adjacent carbons, then they may combine to form -OCH2O-; R<4> is selected from C3-5-cycloalkyl substituted with 0-2 R<3>, phenyl substituted with 0-2 R<3>, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R<3>; R<5> and R<5a> are independently selected from H, C3 and C2H5; R<6> is selected from H, OH, CH3, C2H5, OCH3, OC2H5, and NR<5>R<5a>; R<7> is selected from CH3, C2H5, OCH3, and OC2H5; R<8> is selected from H, cyclopropyl, CH3 and C2H5; and, n is selected from 0, 1, 2, and 3. 3. A compound according to Claim 2, wherein: R<1> is selected from CF3, and C2F5; R<2> is selected from C1-3-alkyl substituted with one R<4>, C2-3-alkenyl substituted with one R<4>, and C2-3-alkynyl substituted with one R<4>; R<3> each, is independently selected from C1-3-alkyl, OH, C1-3-alkoxy, F, Cl, Br, I, NR<5>R<5a>, NO2, CN, C(O)R<6>, NHC(O)R<7>, and NHC(O)NR<5>R<5a>; alternatively, if two R<3> substituents are present and are attached to adjacent carbons, then they may combine to form -OCH2O-; R<4> is selected from C3-5-cycloalkyl substituted with 0-2 R<3>, phenyl substituted with 0-2 R<3>, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R<3>; R<5> and R<5a> are independently selected from H, CH3 and C2H5; R<6> is selected from H, OH, CH3, C2H5, OCH3, OC2H5, and NR<5>R<5a>; R<7> is selected from CH3, C2H5, OCH3, and OC2H5; R<8> is selected from H, CH3 and C2H5; and, n is selected from 0, 1, and 2. 4. A compound according to Claim 3, wherein: R<1> is CF3; R<2> is selected from C1-3-alkyl substituted with one R<4>, C2-3-alkenyl substituted with one R<4>, and C2-5-alkynyl substituted with one R<4>; R<3> each is independently selected from C1-3-alkyl, OH, C1-3-alkoxy, F, Cl, NR<5>R<5a>, NO2, CN, C(O)R<6>, NHC(O)R<7>, and NHC(O)NR<5>R<5a>; alternatively, if two R<3> substituents are present and are attached to adjacent carbons, then they may combine to form -OCH2O-; R<4> is selected from cyclopropyl substituted with 0-1 R<3>, phenyl substituted with 0-2 R<3>, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R<3>, wherein the heterocyclic system is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, and 2-imidazolyl; R<5> and R<5a> are independently selected from H, CH3 and C2H5; R<6> is selected from H, OH, CH3, C2H5, OCH3, OC2H5, and NR<5>R<5a>. R<7> is selected from CH3, C2H5, OCH3, and OC2H5; R<8> is selected from H, CH3 and C2H5; and, n is selected from 1 and 2. 5. A compound according to Claim 4, wherein the compound is of formula Ia:    6. A compound according to Claim 4, wherein the compound is of formula Ib:   7. A compound according to Claim 1, wherein the compound is selected from: (+/-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-chloro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-chloro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-4-cyclopropylethynyl-6-methoxy-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-methoxy-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-methoxy-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-5,6-difluoro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-5,6-difluoro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-4-cyclopropylethynyl-6-fluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-fluoro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-fluoro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1)-quinazolinone; (+/-)-6-fluoro-4-(2'-2-pyridyl)ethyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-fluoro-4-phenylethyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+)-4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (-)-4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+)-E-4-cyclopropylethenyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; and, (-)-6-chloro-4-E-cyclopropylethenyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; or a pharmaceutically acceptable salt thereof. 8. A compound according of formula II:   or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R<2> is C [triple bond] C-R<4a>; R<3> is selected from C1-4-alkyl, OH, C1-4-alkoxy, F, Cl, Br, I, NR<5>R<5a>, NO2, CN, C(O)R<6>, NHC(O)R<7>, and NHC(O)NR<5>R<5a>; R<4a> is selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, and isopentyl; R<5> and R<5a> are independently selected from H and C1-3-alkyl; R<6> is selected from H, OH, C1-4-alkyl, C1-4-alkoxy, and NR<5>R<5a>; R<7> is selected from C1-3-alkyl and C1-3-alkoxy; R<8> is selected from H, C3-5-cycloalkyl, and C1-3-alkyl; and, n is selected from 0, 1, 2, 3, and 4. 9. A compound according to Claim 8, wherein: R<2> is C [triple bond] C-R<4a>; R<3> is selected from C1-4-alkyl, OH, C1-4-alkoxy, F, Cl, Br, I, NR<5>R<5a>, NO2, CN, C(O)R<6>, and NHC(O)R<7>; R<4a> is selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, and isopentyl; R<5> and R<5a> are independently selected from H, CH3 and C2H5; R<6> is selected from H, OH, CH3, C2H5, OCH3, OC2H5, and NR<5>R<5a>; R<7> is selected from CH3, C2H5, OCH3, and OC2H5; R<8> is selected from H, cyclopropyl, CH3 and C2H5; and, n is selected from 0, 1, and 2. 10. A compound according to Claim 9, wherein the compound is of formula IIa:   11. A compound according to Claim 9, wherein the compound is of formula IIb:    12. A compound according to Claim 8, wherein the compound is selected from: (+/-)-6-chloro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-chloro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-4-isopropylethynyl-6-methoxy-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-5,6-difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-5,6-difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-5,6-difluoro-4-isopentyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-fluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-fluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (-)-5,6-difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+)-5,6-difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (-)-5,6-difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; and, (+)-5,6-difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; or a pharmaceutically acceptable salt thereof. 13. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of one of Claims 1-12 or a pharmaceutically acceptable salt form thereof. 14. A method for treating HIV infection, comprising: administering to a host in need of such treatment a therapeutically effective amount of a compound of one of Claims 1-12, or a pharmaceutically acceptable salt form thereof. 15. A method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of: (a) a compound of one of Claims 1-12 or stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salts thereof; and, (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors. 16. A method according to Claim 15, wherein the reverse transcriptase inhibitor is selected from AZT, 3TC, ddI, ddC, d4T, delavirdine, TIBO derivatives, BI-RG-587, nevirapine, L-697 661, LY 73497, Ro 18,893, loviride, trovirdine, MKC-442, and HBY 097, and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, U-140690, and ABT-378. 17. A