Claims
- 1. A compound of formula I: or a pharmaceutically acceptable salt thereof wherein, A is (a) Cl, (b) Br, (c) CN, (d) NO2, or (e) F; R1 is (a) R5, or (b) SO2R9 R2, R3 and R4 may be the same or different and are selected from the group consisting of: (a) H, (b) halo, (c) aryl, (d) S(O)mR6, (e) (C═O)R6, (f) (C═O)OR9, (g) cyano, (h) het, wherein said het is bound via a carbon atom, (i) OR10, (j) Ohet, (k) NR7R8 (l) SR10, (m) Shet, (n) NHCOR12, (o) NHSO2R12, (p) C1-7alkyl which may be partially unsaturated and optionally substituted by one or more substituents of the group R11, OR13, SR10, SR13, NR7R8, halo, (C═O)C1-7alkyl, or SOmR9, and (q) R3 together with R2 or R4 form a carbocyclic or het which may be optionally substituted by NR7R8, or C1-7alkyl which may be optionally substituted by OR14; R5 is (a) (CH2CH2O)iR10, (b) C1-7alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR7R8, R11, SOmR9, or OC2-4alkyl which may be further substituted by het, OR10, or NR7R8, or (c) C3-8cycloalkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from a group consisting of R11, NR7R8, SOmR9, or C1-7alkyl optionally substituted by R11, NR7R8, or SOmR9; R6 is (a) C1-7alkyl, (b) NR7R8, (c) aryl, or (d) het, wherein said het is bound via a carbon atom; R7 and R8 are independently (a) H, (b) aryl, (c) C1-7alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of aryl, NR10R10, R11, SOmR9, CONR10R10, or halo, or; (d) C3-8cycloalkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from a group consisting of R11, NR7R8, SOmR9, or C1-7alkyl optionally substituted by R11, NR7R8, or SOmR9, or (e) R7 and R8 together with the nitrogen to which they are attached form a het; R9 is (a) aryl, (b) het, (c) C3-8cycloalkyl, (d) methyl, or (e) C2-7alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR10R10, R11, SH, CONR10R10, or halo; R10 is (a) H, (b) methyl, or (c) C2-7alkyl optionally substituted by OH; R11 is (a) OR10, (b) Ohet, (c) Oaryl, (d) CO2R10, (e) het, (f) aryl, (g) CN, or (h) C3-8cycloalkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from a group consisting of R11, NR7R8, SOmR9, or C1-7alkyl optionally substituted by R11, NR7R8, or SOmR9; R12 is (a) H, (b) het, (c) aryl, (d) C3-8cycloalkyl, (e) methyl, or (f) C2-7alkyl optionally substituted by NR7R8 or R11; R13 is (a) (P═O)(OR14)2, (b) CO(CH2)nCON(CH3)—(CH2)nSO3−M+, (c) an amino acid, (d) C(═O)aryl, (e) C(═O)C1-7alkyl optionally substituted by NR7R8, aryl, het, CO2H, or O(CH2)nCO2R14, or (f) C(═O)NR7R8 R14 is (a) H, or (b) C1-7alkyl; each i is independently 2, 3, or 4; each n is independently 1, 2, 3, 4 or 5; each m is independently 0, 1, or 2; M is sodium, potassium, or lithium; aryl is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic; wherein any aryl is optionally substituted with one or more substituents selected from the group consisting of halo, OH, cyano, CO2R14, CF3, C1-6alkoxy, and C1-6 alkyl which maybe further substituted by one to three SR14, NR14R14, OR14, or CO2R14; het is a four-(4), five-(5), six-(6), or seven-(7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group; wherein any het is optionally substituted with one or more substituents selected from the group consisting of halo, OH, cyano, phenyl, CO2R14, CF3, C1-6alkoxy, oxo, oxime, and C1-6 alkyl which maybe further substituted by one to three SR14, NR14R14, OR14, or CO2R14.
- 2. The compound of claim 1 wherein A is Cl.
- 3. The compound of claim 1 wherein R1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, carboxymethyl, (C1-7alkoxy)carbonylmethyl, 2-hydroxyethyl, 2-(2-methoxyethoxy)ethyl, 3-(2-tetrahydropyranyloxy)propyl, 2-morpholinoethyl, 2-(diethylamino)ethyl, 2-(dimethylamino)ethyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(1-methylpyrrolidin-2-yl)ethyl, 2-(diisopropylamino)ethyl, 2-pyrrolidin-1-ylethyl, 3-(dimethylamino)propyl, and vinyl.
- 4. The compound of claim 1 wherein R2 is selected from the group consisting of CH2-morpholine, C2-6alkynyl-CH2OH, CH2-(tetrahydro-2H-pyran-4-yl), and (CH2)3OH.
- 5. The compound of claim 4 wherein C2-6alkynyl-CH2OH is structure i:
- 6. The compound of claim 1 which is selected from the group consisting of(1) N-(4-chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (2) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (3) N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (4) N-(4-chlorobenzyl)-6-(4-hydroxy-1-butynyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (5) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (6) N-(4-chlorobenzyl)-8-{[(1R,2R)-1-hydroxy-2-methylcyclohexyl]ethynyl}-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (7) N-(4-chlorobenzyl)-8-(cyclopropylethynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (8) N-(4-chlorobenzyl)-8-[3-(dimethylamino)-1-propynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo 1,4-dihydro-3-cinnolinecarboxamide; (9) N-(4-chlorobenzyl)-1-methyl-4-oxo-8-{4-[(4R)-2-oxo-1,3-oxazolidin-4-yl]-1-butynyl}-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (10) N(4-chlorobenzyl)-8-(4-hydroxy-1-butynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (11) N-(4-chlorobenzyl)-8-[(1-hydroxycyclohexyl)ethynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (12) N-(4-chlorobenzyl)-8-(3,3-dicyclopropyl-3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (13) N-(4-chlorobenzyl)-8-[(3S)-3-hydroxy-1-butynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (14) N-(4-chlorobenzyl)-1-methyl-8-[3-methyl-3-(4-thioxo-1,3,5-triazinan-1-yl)-1-butynyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (15) N-(4-chlorobenzyl)-8-[(3R)-3-hydroxy-1-butynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (16) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-8-{4-[(4R)-2-oxo-1,3-oxazolidin-4-yl]-1-butynyl}-1,4-dihydro-3-cinnolinecarboxamide; (17) N-(4-chlorobenzyl)-8-[3-(1,1-dioxido-4-thiomorpholinyl)-1-propynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (18) N-(4-chlorobenzyl)-8-(5-hydroxy-1-pentynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (19) N-(4-chlorobenzyl)-8-{[(1R,2S)-2-hydroxycyclopentyl]ethynyl}-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (20) N-(4-chlorobenzyl)-8-(3-hydroxy-3-methyl-1-butynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (21) N-(4-chlorobenzyl)-8-[3-(4,5-dichloro-1H-imidazol-1-yl)-1-propynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (22) N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (23) N-(4-chlorobenzyl)-1-methyl-4-oxo-8-(phenylethynyl)-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (24) N-(4-chlorobenzyl)-8-(3-hydroxy-3-phenyl-1-propynyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (25) N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (26) N-(4-chlorobenzyl)-8-(4-hydroxy-1-butynyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (27) N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (28) N-(4-chlorobenzyl)-8-(4-hydroxy-1-butynyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (29) N-(4-chlorobenzyl)-8-[3-(dimethylamino)-1-propynyl]-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (30) N-(4-chlorobenzyl)-1-[3-(methylsulfonyl)propyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (31) N-(4-chlorobenzyl)-1-[3-(methylsulfanyl)propyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (32) N-(4-chlorobenzyl)-1-[(2-hydroxyethoxy)methyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (33) N-(4-chlorobenzyl)-1-{3-[(3-hydroxypropyl)sulfonyl]propyl}-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (34) N-(4-chlorobenzyl)-1-[2-(2-ethoxyethoxy)ethyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (35) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfinyl)methyl]-1,4-dihydro-3-cinnolinecarboxamide; (36) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfonyl)methyl]-1,4-dihydro-3-cinnolinecarboxamide; (37) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfanyl)methyl]-1,4-dihydro-3-cinnolinecarboxamide; (38) N-(4-chlorobenzyl)-1-[(methylsulfanyl)methyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (39) N-(4-chlorobenzyl)-1-{[(4-chlorophenyl)sulfinyl]methyl}-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (40) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-8-(4-thiomorpholinylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (41) N-(4-chlorobenzyl)-8-[(4-hydroxy-1-piperidinyl)methyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (42) N-(4-chlorobenzyl)-8-{[(3R)-3-hydroxypyrrolidinyl]methyl}-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (43) N-(4-chlorobenzyl)-8-[(3-hydroxy-1-piperidinyl)methyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (44) N-(4-chlorobenzyl)-8-(hydroxymethyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (45) N-(4-chlorobenzyl)-8-[(3-cyanobenzyl)amino]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (46) N-(4-chlorobenzyl)-1-methyl-6,8-bis(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (47) N-(4-chlorobenzyl)-1-methyl-8-{[1-methyl-2-(phenylsulfonyl)ethyl]amino}-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (48) N-(4-chlorobenzyl)-8-{[3-(4-methoxyphenyl)-1-methylpropyl]amino}-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (49) 8-amino-N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (50) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-8-[(3-nitrobenzyl)amino]-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (51) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (52) N-(4-chlorobenzyl)-6-(4-hydroxy-1-butyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (53) N-(4-chlorobenzyl)-8-{[(1R,2R)-1-hydroxy-2-methylcyclohexyl]ethyl}-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (54) N-(4-chlorobenzyl)-8-(cyclopropylethyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (55) N-(4-chlorobenzyl)-8-[3-(dimethylamino)-1-propyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (56) N-(4-chlorobenzyl)-1-methyl-4-oxo-8-{4-[(4R)-2-oxo-1,3-oxazolidin-4-yl]-1-butyl}-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (57) N-(4-chlorobenzyl)-8-(4-hydroxy-1-butyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (58) N-(4-chlorobenzyl)-8-[(1-hydroxycyclohexyl)ethyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (59) N-(4-chlorobenzyl)-8-(3,3-dicyclopropyl-3-hydroxy-1-propyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (60) N-(4-chlorobenzyl)-8-[(3S)-3-hydroxy-1-butyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (61) N-(4-chlorobenzyl)-1-methyl-8-[3-methyl-3-(4-thioxo-1,3,5-triazinan-1-yl)-1-butyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (62) N-(4-chlorobenzyl)-8-[(3R)-3-hydroxy-1-butyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (63) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-8-{4-[(4R)-2-oxo-1,3-oxazolidin-4-yl]-1-butyl-}-1,4-dihydro-3-cinnolinecarboxamide; (64) N-(4-chlorobenzyl)-8-[3-(1,1-dioxido-4-thiomorpholinyl)-1-propyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (65) N-(4-chlorobenzyl)-8-(5-hydroxy-1-pentyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (66) N-(4-chlorobenzyl)-8-{[(1R,2S)-2-hydroxycyclopentyl]ethyl}-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (67) N-(4-chlorobenzyl)-8-(3-hydroxy-3-methyl-1-butyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (68) N-(4-chlorobenzyl)-8-[3-(4,5-dichloro-1H-imidazol-1-yl)-1-propyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (69) N-(4-chlorobenzyl)-8-[3-(1H-imidazol-1-yl)-1-propyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (70) N-(4-chlorobenzyl)-8-[3-(1H-imidazol-1-yl)-1-propynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (71) N-(4-chlorobenzyl)-8-(3-hydroxy-1-propyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (72) N-(4-chlorobenzyl)-1-methyl-4-oxo-8-(phenylethyl)-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (73) N-(4-chlorobenzyl)-8-(3-hydroxy-3-phenyl-1-propyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (74) N-(4-chlorobenzyl)-8-(3-hydroxy-1-propyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (75) N-(4-chlorobenzyl)-8-(4-hydroxy-1-butyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (76) N-(4-chlorobenzyl)-8-(3-hydroxy-1-propyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (77) N-(4-chlorobenzyl)-8-(4-hydroxy-1-butyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (78) N-(4-chlorobenzyl)-8-[3-(dimethylamino)-1-propyl]-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; and (79) N-(4-chlorobenzyl)-1-methyl-8-{[methyl(tetrahydro-2-furanylmethyl)amino]methyl}-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide.
- 7. A compound selected from the group consisting of:N-(4-chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; N-(4-chlorobenzyl)-6-(4-hydroxy-1-butynyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; and N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide.
- 8. A composition of matter comprising a pharmaceutically effective amount of a compound of formula (I): or a pharmaceutically acceptable salt thereof wherein, A is (a) Cl, (b) Br, (c) CN, (d) NO2, or (e) F; R1 is (a) R5, or (b) SO2R9 R2, R3 and R4 may be the same or different and are selected from the group consisting of: (a) H, (b) halo, (c) aryl, (d) S(O)mR6, (e) (C═O)R6, (f) (C═O)OR9, (g) cyano, (h) het, wherein said het is bound via a carbon atom, (i) OR10, (j) Ohet, (k) NR7R8 (l) SR10, (m) Shet, (n) NHCOR12, (o) NHSO2R12, (p) C1-7alkyl which may be partially unsaturated and optionally substituted by one or more substituents of the group R11, OR13, SR10, SR13, NR7R8, halo, (C═O)C1-7alkyl, or SOmR9, and (q) R3 together with R2 or R4 form a carbocyclic or het which may be optionally substituted by NR7R8, or C1-7alkyl which may be optionally substituted by OR14; R5 is (a) (CH2CH2O)iR10, (b) C1-7alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR7R8, R11, SOmR9, or OC2-4alkyl which may be further substituted by het, OR10, or NR7R8, or (c) C3-8cycloalkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from a group consisting of R11, NR7R8, SOmR9, or C1-7alkyl optionally substituted by R11, NR7R8, or SOmR9; R6 is (a) C1-7alkyl, (b) NR7R8, (c) aryl, or (d) het, wherein said het is bound via a carbon atom; R7 and R8 are independently (a) H, (b) aryl, (c) C1-7alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of aryl, NR10R10, R11, SOmR9, CONR10R10, or halo, or; (d) C3-8cycloalkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from a group consisting of R11, NR7R8, SOmR9, or C1-7alkyl optionally substituted by R11, NR7R8, or SOmR9, or (e) R7 and R8 together with the nitrogen to which they are attached form a het; R9 is (a) aryl, (b) het, (c) C3-8cycloalkyl, (d) methyl, or (e) C2-7alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR10R10, R11, SH, CONR10R10, or halo; R10 is (a) H, (b) methyl, or (c) C2-7alkyl optionally substituted by OH; R11 is (a) OR10, (b) Ohet, (c) Oaryl, (d) CO2R10, (e) het, (f) aryl, (g) CN, or (h) C3-8cycloalkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from a group consisting of R11, NR7R8, SOmR9, or C1-7alkyl optionally substituted by R11, NR7R8, or SOmR9; R12 is (a) H, (b) het, (c) aryl, (d) C3-8cycloalkyl, (e) methyl, or (f) C2-7alkyl optionally substituted by NR7R8 or R11; R13 is (a) (P═O)(OR14)2, (b) CO(CH2)nCON(CH3)—(CH2)nSO3−M+, (c) an amino acid, (d) C(═O)aryl, or (e) C(═O)C1-7alkyl optionally substituted by NR7R8, aryl, het, CO2H, or O(CH2)nCO2R14; R14 is (a) H, or (b) C1-7alkyl; each i is independently 2, 3, or 4; each n is independently 1, 2, 3, 4 or 5; each m is independently 0, 1, or 2; M is sodium, potassium, or lithium; aryl is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic; wherein any aryl is optionally substituted with one or more substituents selected from the group consisting of halo, OH, cyano, CO2R14, CF3, C1-6alkoxy, and C1-6 alkyl which maybe further substituted by one to three SR14, NR14R14, OR14, or CO2R14; het is a four-(4), five-(5), six-(6), or seven-(7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group; wherein any het is optionally substituted with one or more substituents selected from the group consisting of halo, OH, cyano, phenyl, CO2R14, CF3, C1-6alkoxy, oxo, oxime, and C1-6 alkyl which maybe further substituted by one to three SR14, NR14R14, OR14, or CO2R14; and a pharmaceutically effective carrier.
- 9. The composition of claim 8 wherein A is Cl.
- 10. The compound of claim 8 wherein R1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, carboxymethyl, (C1-7alkoxy)carbonylmethyl, 2-hydroxyethyl, 2-(2-methoxyethoxy)ethyl, 3-(2-tetrahydropyranyloxy)propyl, 2-morpholinoethyl, 2-(diethylamino)ethyl, 2-(dimethylamino)ethyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(1-methylpyrrolidin-2-yl)ethyl, 2-(diisopropylamino)ethyl, 2-pyrrolidin-1-ylethyl, 3-(dimethylamino)propyl, and vinyl.
- 11. The compound of claim 8 wherein R2 is selected from the group consisting of CR2-morpholine, C2-6alkynyl-CH2OH, CH2-(tetrahydro-2H-pyran-4-yl), and (CH2)3OH.
- 12. The compound of claim 11 wherein C2-6alkynyl-CH2OH is structure i:
- 13. The compound of claim 8 which is selected from the group consisting of(1) N-(4-chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (2) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (3) N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (4) N-(4-chlorobenzyl)-6-(4-hydroxy-1-butynyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (5) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (6) N-(4-chlorobenzyl)-8-{[(1R,2R)-1-hydroxy-2-methylcyclohexyl]ethynyl}-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (7) N-(4-chlorobenzyl)-8-(cyclopropylethynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (8) N-(4-chlorobenzyl)-8-[3-(dimethylamino)-1-propynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (9) N-(4-chlorobenzyl)-1-methyl-4-oxo-8-{4-[(4R)-2-oxo-1,3-oxazolidin-4-yl]-1-butynyl}-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (10) N-(4-chlorobenzyl)-8-(4-hydroxy-1-butynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (11) N-(4-chlorobenzyl)-8-[(1-hydroxycyclohexyl)ethynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (12) N-(4-chlorobenzyl)-8-(3,3-dicyclopropyl-3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (13) N-(4-chlorobenzyl)-8-[(3S)-3-hydroxy-1-butynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (14) N-(4-chlorobenzyl)-1-methyl-8-[3-methyl-3-(4-thioxo-1,3,5-triazinan-1-yl)-1-butynyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (15) N-(4-chlorobenzyl)-8-[(3R)-3-hydroxy-1-butynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (16) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-8-{4-[(4R)-2-oxo-1,3-oxazolidin-4-yl]-1-butynyl}-1,4-dihydro-3-cinnolinecarboxamide; (17) N-(4-chlorobenzyl)-8-[3-(1,1-dioxido-4-thiomorpholinyl)-1-propynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (18) N-(4-chlorobenzyl)-8-(5-hydroxy-1-pentynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (19) N-(4-chlorobenzyl)-8-{[(1R,2S)-2-hydroxycyclopentyl]ethynyl}-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (20) N-(4-chlorobenzyl)-8-(3-hydroxy-3-methyl-1-butynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (21) N-(4-chlorobenzyl)-8-[3-(4,5-dichloro-1H-imidazol-1-yl)-1-propynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (22) N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (23) N-(4-chlorobenzyl)-1-methyl-4-oxo-8-(phenylethynyl)-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (24) N-(4-chlorobenzyl)-8-(3-hydroxy-3-phenyl-1-propynyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (25) N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (26) N-(4-chlorobenzyl)-8-(4-hydroxy-1-butynyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (27) N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (28) N-(4-chlorobenzyl)-8-(4-hydroxy-1-butynyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (29) N-(4-chlorobenzyl)-8-[3-(dimethylamino)-1-propynyl]-1-methyl-4-oxo-6-(tetrahydro-2H-pyran -4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (30) N-(4-chlorobenzyl)-1-[3-(methylsulfonyl)propyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (31) N-(4-chlorobenzyl)-1-[3-(methylsulfanyl)propyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (32) N-(4-chlorobenzyl)-1-[(2-hydroxyethoxy)methyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (33) N-(4-chlorobenzyl)-1-{3-[(3-hydroxypropyl)sulfonyl]propyl}-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (34) N-(4-chlorobenzyl)-1-[2-(2-ethoxyethoxy)ethyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (35) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfinyl)methyl]-1,4-dihydro-3-cinnolinecarboxamide; (36) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfonyl)methyl]-1,4-dihydro-3-cinnolinecarboxamide; (37) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfanyl)methyl]-1,4-dihydro-3-cinnolinecarboxamide; (38) N-(4-chlorobenzyl)-1-[(methylsulfanyl)methyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (39) N-(4-chlorobenzyl)-1-{[(4-chlorophenyl)sulfinyl]methyl}-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (40) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl-4-oxo-8-(4-thiomorpholinylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (41) N-(4-chlorobenzyl)-8-[(4-hydroxy-1-piperidinyl)methyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (42) N-(4-chlorobenzyl)-8-{[(3R)-3-hydroxypyrrolidinyl]methyl}-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (43) N-(4-chlorobenzyl)-8-[(3-hydroxy-1-piperidinyl)methyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (44) N-(4-chlorobenzyl)-8-(hydroxymethyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (45) N-(4-chlorobenzyl)-8-[(3-cyanobenzyl)amino]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (46) N-(4-chlorobenzyl)-1-methyl-6,8-bis(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (47) N-(4-chlorobenzyl)-1-methyl-8-{[1-methyl-2-(phenylsulfonyl)ethyl]amino}-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (48) N-(4-chlorobenzyl)-8-{[3-(4-methoxyphenyl)-1-methylpropyl]amino}-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (49) 8-amino-N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (50) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-8-[(3-nitrobenzyl)amino]-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (51) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (52) N-(4-chlorobenzyl)-6-(4-hydroxy-1-butyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (53) N-(4-chlorobenzyl)-8-{[(1R,2R)-1-hydroxy-2-methylcyclohexyl]ethyl}-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (54) N-(4-chlorobenzyl)-8-(cyclopropylethyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (55) N-(4-chlorobenzyl)-8-[3-(dimethylamino)-1-propyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (56) N-(4-chlorobenzyl)-1-methyl-4-oxo-8-{4-[(4R)-2-oxo-1,3-oxazolidin-4-yl]-1-butyl}-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (57) N-(4-chlorobenzyl)-8-(4-hydroxy-1-butyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (58) N-(4-chlorobenzyl)-8-[(1-hydroxycyclohexyl)ethyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (59) N-(4-chlorobenzyl)-8-(3,3-dicyclopropyl-3-hydroxy-1-propyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (60) N-(4-chlorobenzyl)-8-[(3S)-3-hydroxy-1-butyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (61) N-(4-chlorobenzyl)-1-methyl-8-[3-methyl-3-(4-thioxo-1,3,5-triazinan-1-yl)-1-butyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (62) N-(4-chlorobenzyl)-8-[(3R)-3-hydroxy-1-butyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (63) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-8-{4-[(4R)-2-oxo-1,3-oxazolidin-4-yl]-1-butyl}-1,4-dihydro-3-cinnolinecarboxamide; (64) N-(4-chlorobenzyl)-8-[3-(1,1-dioxido-4-thiomorpholinyl)-1-propyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (65) N-(4-chlorobenzyl)-8-(5-hydroxy-1-pentyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (66) N-(4-chlorobenzyl)-8-{[(1R,2S)-2-hydroxycyclopentyl]ethyl}-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (67) N-(4-chlorobenzyl)-8-(3-hydroxy-3-methyl-1-butyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (68) N-(4-chlorobenzyl)-8-[3-(4,5-dichloro-1H-imidazol-1-yl)-1-propyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (69) N-(4-chlorobenzyl)-8-[3-(1H-imidazol-1-yl)-1-propyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (70) N-(4-chlorobenzyl)-8-[3-(1H-imidazol-1-yl)-1-propynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (71) N-(4-chlorobenzyl)-8-(3-hydroxy-1-propyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (72) N-(4-chlorobenzyl)-1-methyl-4-oxo-8-(phenylethyl)-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (73) N-(4-chlorobenzyl)-8-(3-hydroxy-3-phenyl-1-propyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (74) N-(4-chlorobenzyl)-8-(3-hydroxy-1-propyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (75) N-(4-chlorobenzyl)-8-(4-hydroxy-1-butyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (76) N-(4-chlorobenzyl)-8-(3-hydroxy-1-propyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (77) N-(4-chlorobenzyl)-8-(4-hydroxy-1-butyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; (78) N-(4-chlorobenzyl)-8-[3-dimethylamino)-1-propyl]-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-cinnolinecarboxamide; and (79) N-(4-chlorobenzyl)-1-methyl-8-{[methyl(tetrahydro-2-furanylmethyl)amino]methyl}-6-(4morpholinylmethyl)-4-oxo-1,4-dihydro-3-cinnolinecarboxamide.
- 14. A method of treating a viral infection, comprising administering to a mammal in need of such treatment, a compound of claim 1.
- 15. The method according to claim 14 wherein said viral infection is a herpes virus infection.
- 16. The method according to claim 14 wherein said mammal is a human.
- 17. The method according to claim 14 wherein said mammal is a livestock or companion animal.
- 18. The method according to claim 15 wherein the infection is herpes simplex virus type 1, 2, 6, 7, or 8, varicella zoster virus, human cytomegalovirus, or epstein-Barr virus.
- 19. The method according to claim 14 wherein the amount administered is from about 0.1 to about 300 mg/kg of body weight.
- 20. The method according to claim 19 wherein the amount administered is from about 1 to about 30 mg/kg of body weight.
- 21. The method according to claim 14 wherein the compound is administered parenterally, intranasally, topically, intravaginally, orally, or rectally.
- 22. A method for inhibiting a herpes viral DNA polymerase, comprising contacting, in vitro or in vivo, the polymerase with an effective inhibitory amount of a compound of claim 1.
- 23. The method of claim 22 wherein the polymerase and the compound are contacted in vitro.
- 24. The method of claim 23 wherein the polymerase and the compound are contacted in vivo.
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the following provisional application: U.S. Serial No. 60/191,291, filed Mar. 21, 2000.
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Provisional Applications (1)
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