US2004142928A1PendingUtilityA1
Heterocycle carboxamides as antiviral agents
Priority: Jul 12, 2000Filed: Dec 23, 2003Published: Jul 22, 2004
Est. expiryJul 12, 2020(expired)· nominal 20-yr term from priority
Inventors:Gordon L. BundyFred Lawrence CiskeMichael James GeninSteven HeasleyScott D. LarsenByung-Ho LeePaul D. MayJohn R. PalmerMark Edward SchnuteValerie A. VaillancourtAtli ThorarensenAllison WolfNancy WicnienskiDavid Wilhite
A61P 43/00A61P 31/22C07D 279/02C07D 265/22C07D 333/58C07D 311/22C07D 513/04C07D 285/16C07D 471/04C07D 495/04
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Claims
Abstract
The present invention provides a compound of formula I which is useful as antiviral agents, in particular, as agents against viruses of the herpes family.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of formula I,
wherein,
X is Cl, Br, F, CN, or NO 2 ;
G is (a) C 1-4 alkyl which is fully saturated or partially unsaturated and is substituted by hydroxy, or
(b) C 1-4 alkyl substituted by NR 1 R 2 or 4-tetrahydropyran;
R 1 is C 2-7 alkyl substituted by hydroxy, C 1-4 alkoxy, heteroaryl, or aryl;
R 2 is hydrogen or C 1-7 alkyl;
or R 1 and R 2 together with the nitrogen to which they are attached form morpholine which may be optionally substituted by aryl or C 1-7 alkyl; or pyrrolidine substituted by hydroxy;
W is a heterocycle of formula W1, W2, W3, W4, W5, W6, W7, W8, W9, W10, W11, W12, W13, W14, W15, W16, W17, W18, W19, W20, W21 or W22
A is CR 4 or nitrogen;
B is CR 5 or nitrogen;
C is CR 6 or nitrogen;
D is CR 8 or nitrogen;
E and F are such that one is oxygen and the other is C(═O);
J is NR 7 or oxygen;
K and L are defined such that (a) K is CR and L is CR 6 , or
(b) K is absent and L is sulfur;
M is oxygen, sulfur, or S(O) m ;
Y is oxygen or sulfur;
with the provisos that:
when W is of formula W3 then at least one of A, B, or C is nitrogen and R 7 is other than H, and if C is nitrogen then A, B or A and B are nitrogen;
when W is of formula W4 then at least one of A, B, or C is nitrogen;
when W is of formula W9 then at least two of A, B, or C is nitrogen;
when W is of formula W16 and J is oxygen then R 7 is other than H;
when W is of formula W16 then J is other than NH;
when W is of formula W19, A is nitrogen, G is morpholinylmethyl, and X is chloro then R 8 is other than H;
when W is of formula W20 then at least one of A or D is nitrogen;
R4 is H, halogen, or C 1-4 alkyl optionally substituted by one to three halogens;
R 5 is (a) H,
(b) halo,
(c) OR 12 ,
(d) SR 12 ,
(e) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR 12 , SR 12 , NR 10 R 11 , or halo,
(f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR 12 , SR 12 , or NR 10 R 11 ,
(g) (C═O)R 9 ,
(h) S(O) m R 9 ,
(i) (C═O)OR 2 ,
(j) NHSO 2 R 9 ,
(k) nitro, or
(l) cyano;
R 6 is (a) H,
(b) halo,
(c) aryl,
(d) het,
(e) OR 12 ,
(f) SR 12 ,
(g) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR 12 , SR 12 , NR 10 R 11 , aryl, halo, C 3-8 cycloalkyl optionally substituted by OR 2 , or het attached through a carbon atom,
(h) NR 10 R 11 ,
(i) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR 12 , SR 12 , or NR 10 R 11 ,
(j) (C═O)R 9 ,
(k) S(O) m R 9 ,
(l) (C═O)OR
(m) NHSO 2 R 9 ,
(n) nitro, or
(o) cyano;
R 7 is (a) H,
(b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR 2 , SR 2 , NR 10 R 11 , or halo,
(c) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR 12 , SR 12 , or NR 10 R 11 ,
(d) aryl, or
(e) het;
R 8 is (a) H,
(b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR 12 , SR 12 , NR 10 R 11 , or halo,
(c) OR 12 , or
(d) SR 12 ;
R 9 is (a) C 1-7 alkyl,
(b) NR 10 R 11 ,
(c) aryl, or
(d) het, wherein said het is bound through a carbon atom;
R 10 and R 11 are independently
(a) H,
(b) aryl,
(c) C 1-7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from CONR 2 R 2 , CO 2 R 2 , het, aryl, cyano, or halo,
(d) C 2-7 alkyl which may be partially unsaturated and is substituted by one or more substituents selected from NR 2 R 2 , OR 2 , or SR 2 ,
(e) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR 2 , SR 2 , or NR 2 R 2 , or
(f) R 10 and R 11 together with the nitrogen to which they are attached form a het;
R 12 is (a) H,
(b) aryl,
(c) het
(d) C 1-7 alkyl optionally substituted by aryl, or halogen,
(e) C 2-7 alkyl substituted by OR 2 , SR 2 , or NR 2 R 2 , or
(f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR 2 , SR 2 , or NR 2 R 2 ;
each m is independently 1 or 2;
aryl is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic, and aryl maybe optionally substituted with one or more substituents selected from halo, OH, cyano, NR 2 R 2 , CO 2 R 2 , CF 3 , C 1-6 alkoxy, and C 1-6 alkyl which maybe further substituted by one to three SR 2 , NR 2 R 2 , OR 2 , or CO 2 R 2 groups;
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 oxygen, sulfur, or nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group, and het may be optionally substituted with one or more substituents selected from halo, OH, cyano, phenyl, CO 2 R 2 , CF 3 , C 1-6 alkoxy, oxo, oxime, and C 1-6 alkyl which may be further substituted by one to three SR 2 , NR 2 R 2 , OR 2 , or CO 2 R 2 groups;
halo or halogen is F, Cl, Br, I;
1 represents the point of attachment between W and G;
2 represents the point of attachment between W and the carbonyl group of Formula (I);
and a pharmaceutically acceptable salt thereof.
2 . A compound of claim 1 wherein W is of the formula W1.
3 . A compound of claim 2 wherein W is of the formula W1.1.
4 . A compound of claim 1 wherein W is of the formula W2.
5 . A compound of claim 1 wherein W is of the formula W3.
6 . A compound of claim 5 wherein W is of the formula W3.1.
7 . A compound of claim 5 wherein W is of the formula W3.2.
8 . A compound of claim 5 wherein W is of the formula W3.3.
9 . A compound of claim 5 wherein W is of the formula W3.4.
10 . A compound of claim 1 wherein W is of the formula W4.
11 . A compound of claim 10 wherein W is of the formula W4.1.
12 . A compound of claim 10 wherein W is of the formula W4.2.
13 . A compound of claim 1 wherein W is of the formula W5.
14 . A compound of claim 1 wherein W is of the formula W6.
15 . A compound of claim 14 wherein W is of the formula W6.1.
16 . A compound of claim 14 wherein W is of the formula W6.2.
17 . A compound of claim 14 wherein W is of the formula W6.3.
18 . A compound of claim 14 wherein W is of the formula W6.4.
19 . A compound of claim 14 wherein W is of the formula W6.5.
20 . A compound of claim 1 wherein W is of the formula W7.
21 . A compound of claim 20 wherein W is of the formula W7.1.
22 . A compound of claim 20 wherein W is of the formula W7.2.
23 . A compound of claim 20 wherein W is of the formula W7.3.
24 . A compound of claim 1 wherein W is of the formula W8.
25 . A compound of claim 24 wherein W is of the formula W8.1.
26 . A compound of claim 24 wherein W is of the formula W8.2.
27 . A compound of claim 24 wherein W is of the formula W8.8.
28 . A compound of claim 24 wherein W is of the formula W8.9.
29 . A compound of claim 1 wherein W is of the formula W9.
30 . A compound of claim 1 wherein W is of the formula W10.
31 . A compound of claim 30 wherein W is of the formula W10.1.
32 . A compound of claim 30 wherein W is of the formula W10.2.
33 . A compound of claim 1 wherein W is of the formula W11.
34 . A compound of claim 1 wherein W is of the formula W12.
35 . A compound of claim 1 wherein W is of the formula W13.
36 . A compound of claim 35 wherein W is of the formula W13.4.
37 . A compound of claim 1 wherein W is of the formula W14.
38 . A compound of claim 37 wherein W is of the formula W14.1.
39 . A compound of claim 37 wherein W is of the formula W14.8.
40 . A compound of claim 1 wherein W is of the formula W15.
41 . A compound of claim 1 wherein W is of the formula W16.
42 . A compound of claim 41 wherein W is of the formula W16.1.
43 . A compound of claim 1 wherein W is of the formula W17.
44 . A compound of claim 1 wherein W is of the formula W18.
45 . A compound of claim 1 wherein W is of the formula W19.
46 . A compound of claim 45 wherein W is of the formula W19.1.
47 . A compound of claim 45 wherein W is of the formula W19.2.
48 . A compound of claim 1 wherein W is of the formula W20.
49 . A compound of claim 48 wherein W is of the formula W20.1.
50 . A compound of claim 48 wherein W is of the formula W20.2.
51 . A compound of claim 1 wherein W is of the formula W21.
52 . A compound of claim 1 wherein W is of the formula W22.
53 . A compound of claim 52 wherein W is of the formula W22.2.
54 . The compound according to claim 1 , wherein X is Cl.
55 . The compound according to claim 1 wherein G is 4-morpholinylmethyl.
56 . The compound according to claim 1 wherein G is 3-hydroxy-1-propynyl.
57 . The compound according to claim 1 wherein G is tetrahydro-2H-pyran-4-ylmethyl.
58 . The compound according to claim 1 wherein G is 3-hydroxypropyl.
59 . A compound according to claim 1 which is:
(1) N-(4-chlorobenzyl)-5-hydroxy-3-(3-hydroxy-1-propynyl)-2-oxo-2H-chromene-6-carboxamide;
(2) N-(4-chlorobenzyl)-5-hydroxy-3-(3-hydroxypropyl)-2-oxo-2H-chromene-6-carboxamide;
(3) N-(4-chlorobenzyl)-5-hydroxy-3-(4-morpholinylmethyl)-2-oxo-2H-chromene-6-carboxamide;
(4) N-(4-chlorobenzyl)-5-hydroxy-4-methyl-3,8-bis(4-morpholinylmethyl)-2-oxo-2H-chromene-6-carboxamide;
(5) N-(4-chlorobenzyl)-5-hydroxy-3-(3-hydroxy-1-propynyl)-1-methyl-2-oxo-1,2-dihydro-6-quinolinecarboxamide;
(6) N-(4-chlorobenzyl)-5-hydroxy-3-(3-hydroxypropyl)-1-methyl-2-oxo-1,2-dihydro-6-quinolinecarboxamide;
(7) N-(4-chlorobenzyl)-5-hydroxy-1-methyl-3-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-6-quinolinecarboxamide;
(8) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxamide;
(9) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-methyl-4-oxo-1,4-dihydro[1,7]-naphthyridine-3-carboxamide;
(10) N-(4-chlorobenzyl)-1-methyl-6,8-bis(morpholin-4-ylmethyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxamide;
(11) N-(4-chlorobenzyl)-8-ethoxy-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxamide;
(12) N-(4-chlorobenzyl)-8-ethoxy-6-(3-hydroxypropyl)-1-methyl-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxamide;
(13) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxamide;
(14) 8-chloro-N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro1,7]naphthyridine-3-carboxamide;
(15) N-(4-chlorobenzyl)-8-ethoxy-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxamide;
(16) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-methyl-4-oxo-1,4-dihydro[1,5]-naphthyridine-3-carboxamide;
(17) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro[1,5]naphthyridine-3-carboxamide;
(18) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro[1,5]naphthyridine-3-carboxamide;
(19) N-(4-chlorobenzyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro[1,5]naphthyridine-3-carboxamide;
(20) N-(4-chlorobenzyl)-8-ethyl-3-(4-morpholinylmethyl)-5-oxo-5,8-dihydropyrido[2,3-c]pyridazine-6-carboxamide;
(21) N-(4-chlorobenzyl)-2-(3-hydroxypropyl)-5-methyl-8-oxo-5,8-dihydropyrido[3,2-d]pyrimidine-7-carboxamide;
(22) N-(4-chlorobenzyl)-2-(3-hydroxy-1-propynyl)-5-methyl-8-oxo-5,8-dihydropyrido[3,2-d]pyrimidine-7-carboxamide;
(23) N-(4-chlorobenzyl)-5-methyl-2-(4-morpholinylmethyl)-8-oxo-5,8-dihydropyrido[3,2-d]pyrimidine-7-carboxamide;
(24) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxamide;
(25) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-methyl-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxamide;
(26) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxamide;
(27) N-(4-chlorobenzyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxamide;
(28) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-1,4-dihydropyrido[3,4-c]pyridazine-3-carboxamide;
(29) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydropyrido[3,4-c]pyridazine-3-carboxamide;
(30) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-methyl-4-oxo-1,4-dihydropyrido[3,4-c]pyridazine-3-carboxamide;
(31) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydropyrido[3,4-c]pyridazine-3-carboxamide;
(32) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydropyrido[3,4-c]pyridazine-3-carboxamide;
(33) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydropyrido[3,4-c]-pyridazine-3-carboxamide;
(34) N-(4-chlorobenzyl)-7-(3-hydroxy-1-propynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;
(35) N-(4-chlorobenzyl)-7-(3-hydroxypropyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;
(36) N-(4-chlorobenzyl)-7-(4-morpholinylmethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;
(37) N-(4-chlorobenzyl)-4-hydroxy-7-(3-hydroxy-1-propynyl)-2-oxo-2H-pyrido[1,2-a]pyrimidine-3-carboxamide;
(38) N-(4-chlorobenzyl)-2-hydroxy-7-(3-hydroxypropyl)-4-oxo-4H-pyrido[1,2-a]-pyrimidine-3-carboxamide;
(39) N-(4-chlorobenzyl)-7-(3-hydroxypropyl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-3-carboxamide;
(40) N-(4-chlorobenzyl)-7-(3-hydroxy-1-propynyl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-3-carboxamide;
(41) N-(4-chlorobenzyl)-7-(4-morpholinylmethyl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-3-carboxamide;
(42) N-(4-chlorobenzyl)-7-(3-hydroxy-1-propynyl)-4-oxo-4H-pyrimido[1,2-b]pyridazine-3-carboxamide;
(43) N-(4-chlorobenzyl)-7-(3-hydroxypropyl)-4-oxo-4H-pyrimido[1,2-b]pyridazine-3-carboxamide;
(44) N-(4-chlorobenzyl)-4-oxo-7-(tetrahydro-2H-pyran-4-ylmethyl)-4H-pyrimido[1,2-b]pyridazine-3-carboxamide;
(45) N-(4-chlorobenzyl)-7-(4-morpholinylmethyl)-4-oxo-4H-pyrimido[1,2-b]pyridazine-3-carboxamide;
(46) N-(4-chlorobenzyl)-7-(3-hydroxypropyl)-4-oxo-4H-pyrimido[1,2-a]pyrimidine-3-carboxamide;
(47) N-(4-chlorobenzyl)-7-(3-hydroxy-1-propynyl)-4-oxo-4H-pyrimido[1,2-a]pyrimidine-3-carboxamide;
(48) N-(4-chlorobenzyl)-4-oxo-7-(tetrahydro-2H-pyran-4-ylmethyl)-4H-pyrimido[1,2-a]pyrimidine-3-carboxamide;
(49) N-(4-chlorobenzyl)-7-(4-morpholinylmethyl)-4-oxo-4H-pyrimido[1,2-a]pyrimidine-3-carboxamide;
(50) N-(4-chlorobenzyl)-2-(3-hydroxypropyl)-8-oxo-8H-pyrimido[1,2-b][1,2,4]triazine-7-carboxamide;
(51) N-(4-chlorobenzyl)-2-(3-hydroxy-1-propynyl)-8-oxo-8H-pyrimido[1,2-b][1,2,4]triazine-7-carboxamide;
(52) N-(4-chlorobenzyl)-7-(4-morpholinylmethyl)-4-oxo-4H-quinolizine-3-carboxamide;
(53) N-(4-chlorobenzyl)-7-(3-hydroxypropyl)-4-oxo-4H-quinolizine-3-carboxamide;
(54) N-(4-chlorobenzyl)-7-(3-hydroxy-1-propynyl)-4-oxo-4H-quinolizine-3-carboxamide;
(55) N-(4-chlorobenzyl)-7-(3-hydroxy-1-propynyl)-4-oxo-4H-pyrido[1,2-a]pyrazine-3-carboxamide;
(56) N-(4-chlorobenzyl)-7-(3-hydroxypropyl)-4-oxo-4H-pyrido[1,2-a]pyrazine-3-carboxamide;
(57) N-(4-chlorobenzyl)-7-(4-morpholinylmethyl)-4-oxo-4H-pyrido[1,2-a]pyrazine-3-carboxamide;
(58) N-(4-chlorobenzyl)-3-(4-morpholinylmethyl)-6-oxo-6H-pyrido[1,2-a]pyrimidine-7-carboxamide;
(59) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-4H-chromene-3-carboxamide;
(60) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-4H-chromene-3-carboxamide;
(61) N-(4-chlorobenzyl)-6-(((3R)-3-hydroxypyrrolidinyl)methyl)-4-oxo-4H-chromene-3-carboxamide;
(62) N-(4-chlorobenzyl)-6,8-bis(4-morpholinylmethyl)-4-oxo-4H-chromene-3-carboxamide;
(63) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-4H-chromene-3-carboxamide;
(64) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-4H-pyrano[2,3-b]pyridine-3-carboxamide;
(65) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-4H-pyrano[2,3-b]pyridine-3-carboxamide;
(66) N-(4-chlorobenzyl)-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-4H-pyrano[2,3-b]pyridine-3-carboxamide;
(67) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-4H-pyrano[2,3-b]pyridine-3-carboxamide;
(68) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-4H-thiochromene-3-carboxamide;
(69) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-4H-thiopyrano[2,3-b]pyridine-3-carboxamide;
(70) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-4H-thiopyrano[2,3-b]pyridine-3-carboxamide;
(71) N-(4-chlorobenzyl)-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-4H-thiopyrano[2,3-b]pyridine-3-carboxamide;
(72) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-4H-thiopyrano[2,3-b]pyridine-3-carboxamide;
(73) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-4H-1,2-benzoxazine-3-carboxamide;
(74) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-4H-1,2-benzoxazine-3-carboxamide;
(75) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-4H-1,2-benzoxazine-3-carboxamide;
(76) N-(4-chlorobenzyl)-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-4H-1,2-benzoxazine-3-carboxamide;
(77) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-4H-1,2-benzthiazine-3-carboxamide;
(78) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-4H-1,2-benzthiazine-3-carboxamide;
(79) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-4H-1,2-benzthiazine-3-carboxamide;
(80) N-(4-chlorobenzyl)-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-4H-1,2-benzthiazine-3-carboxamide;
(81) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-1-methyl-1H-2,1-benzothiazine-3-carboxamide 2,2-dioxide;
(82) N-(4-chlorobenzyl)-4-hydroxy-1-methyl-6-(4-morpholinylmethyl)-1H-2,1-benzothiazine-3-carboxamide 2,2-dioxide;
(83) N-(4-chlorobenzyl)-4-methyl-7-(4-morpholinylmethyl)-4H-1,4-benzothiazine-2-carboxamide 1-oxide;
(84) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-1H-4, 1,2-benzothiadiazine-3-carboxamide 4,4-Dioxide;
(85) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-1H-thieno[2,3-e][1,3,4]thiadiazine-3-carboxamide 4,4-dioxide;
(86) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-1H-thieno[2,3-e][1,3,4]thiadiazine-3-carboxamide 4,4-dioxide;
(87) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1H-thieno[2,3-e][1,3,4]thiadiazine-3-carboxamide 4,4-dioxide;
(88) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1H-thieno[2,3-e][1,3,4]thiadiazine-3-carboxamide 4,4-dioxide;
(89) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-methyl-1H-thieno[2,3-e][1,3,4]-thiadiazine-3-carboxamide 4,4-dioxide;
(90) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-1H-thieno[2,3-e][1,3,4]thiadiazine-3-carboxamide 4,4-dioxide;
(91) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1,8-dimethyl-4,7-dioxo-1,4,7,8-tetrahydro [1,8]naphthyridine-3-carboxamide;
(92) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1,8-dimethyl-4,7-dioxo-1,4,7,8-tetrahydro[1,8]naphthyridine-3-carboxamide;
(93) N-(4-chlorobenzyl)-1,8-dimethyl-6-(4-morpholinylmethyl)-4,7-dioxo-1,4,7,8-tetrahydro[1,8]naphthyridine-3-carboxamide;
(94) N-(4-chlorobenzyl)-7-(3-hydroxy-1-propynyl)-4-oxo-4H-pyrido[2, 1-c][1,2,4]triazine-3-carboxamide;
(95) N-(4-chlorobenzyl)-7-(3-hydroxypropyl)-4-oxo-4H-pyrido[2, 1-c][1,2,4]triazine-3-carboxamide;
(96) N-(4-chlorobenzyl)-7-(4-morpholinylmethyl)-4-oxo-4H-pyrido[2, 1-c][1,2,4]triazine-3-carboxamide;
(97) N-(4-chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)-1-benzothiophene-5-carboxamide;
(98) N-(4-chlorobenzyl)-4-hydroxy-2-(3-hydroxypropyl)-1-benzothiophene-5-carboxamide;
(99) N-(4-chlorobenzyl)-2-(4-morpholinylmethyl)-5-oxo-5H-[1,3]thiazolo[3,2-a]-pyrimidine-6-carboxamide;
(100) N-(4-chlorobenzyl)-5-hydroxy-2-(4-morpholinylmethyl)-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxamide;
(101) N-(4-chlorobenzyl)-4-methyl-2-(4-morpholinylmethyl)-7-oxo-4,7-dihydro[1,3]thiazolo[5,4-b]pyridine-6-carboxamide;
(102) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydrothieno[2,3-c]pyridazine-3-carboxamide;
(103) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-methyl-4-oxo-1,4-dihydrothieno[2,3-c]pyridazine-3-carboxamide;
(104) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydrothieno[2,3-c]pyridazine-3-carboxamide;
(105) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-phenyl-1,4-dihydrothieno[2,3-c]pyridazine-3-carboxamide;
(106) N-(4-chlorobenzyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydrothieno[2,3-c]pyridazine-3-carboxamide;
(107) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxyprop-1-ynyl)-1-methyl-1H-thieno[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide; or
a pharmaceutically acceptable salt thereof.
60 . A compound according to claim 1 which is:
(1) N-(4-chlorobenzyl)-7-(3-hydroxy-1-propynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;
(2) N-(4-chlorobenzyl)-5-hydroxy-2-(4-morpholinylmethyl)-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxamide;
(3) N-(4-chlorobenzyl)-4-hydroxy-7-(3-hydroxy-1-propynyl)-2-oxo-2H-pyrido[1,2-a]pyrimidine-3-carboxamide;;
(4) N-(4-chlorobenzyl)-2-(4-morpholinylmethyl)-5-oxo-5H-[1,3]thiazolo[3,2-a]-pyrimidine-6-carboxamide;
(5) N-(4-chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)-1-benzothiophene-5-carboxamide;
(6): N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-4H-chromene-3-carboxamide;
(7) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-4H-1,2-benzoxazine-3-carboxamide;
(8) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxamide;
(9) N-(4-chlorobenzyl)-4-methyl-2-(4-morpholinylmethyl)-7-oxo-4,7-dihydro[1,3]thiazolo[5,4-b]pyridine-6-carboxamide;
(10) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxyprop-1-ynyl)-1-methyl-1H-thieno[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide;
(11) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-1H-4, 1,2-benzothiadiazine-3-carboxamide 4,4-Dioxide;
(12) 8-chloro-N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro 1,7]naphthyridine-3-carboxamide;
(13) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxamide;
(14) N-(4-chlorobenzyl)-1-methyl-6,8-bis(morpholin-4-ylmethyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxamide;
(15)-N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-1-methyl-1H-2,1-benzothiazine-3-carboxamide 2,2-dioxide;
(16) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-1H-thieno[2,3-e][1,3,4]thiadiazine-3-carboxamide 4,4-dioxide;
(17) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro[1,5]naphthyridine-3-carboxamide;
(18) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-phenyl-1,4-dihydrothieno[2,3-c]pyridazine-3-carboxamide;
(19) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-4H-chromene-3-carboxamide;
(20) N-(4-chlorobenzyl)-6,8-bis(4-morpholinylmethyl)-4-oxo-4H-chromene-3-carboxamide;
(21) N-(4-chlorobenzyl)-6-(((3R)-3-hydroxypyrrolidinyl)methyl)-4-oxo-4H-chromene-3-carboxamide; or
a pharmaceutically acceptable salt thereof.
61 . The compound according to claim 1 which is:
(1) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-1H-4, 1,2-benzothiadiazine-3-carboxamide 4,4-Dioxide;
(2) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-1-methyl-1H-2,1-benzothiazine-3-carboxamide 2,2-dioxide;
(3) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-1H-thieno[2,3-e][1,3,4]thiadiazine-3-carboxamide 4,4-dioxide;
(4) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro[1,5]naphthyridine-3-carboxamide; or
or a pharmaceutically acceptable salt thereof.
62 . A compound according to claim 1 which is:
(1) N-(4-chlorobenzyl)-4-hydroxy-7-(3-hydroxy-1-propynyl)-2-oxo-2H-pyrido[1,2-a]pyrimidine-3-carboxamide;
(2) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-4H-chromene-3-carboxamide;
(3) 8-chloro-N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro 1,7]naphthyridine-3-carboxamide;
(4) N-(4-chlorobenzyl)-1-methyl-6,8-bis(morpholin-4-ylmethyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxamide;
(5) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-4H-chromene-3-carboxamide;
(6) N-(4-chlorobenzyl)-6,8-bis(4-morpholinylmethyl)-4-oxo-4H-chromene-3-carboxamide;
(7) N-(4-chlorobenzyl)-6-(((3R)-3-hydroxypyrrolidinyl)methyl)-4-oxo-4H-chromene-3-carboxamide; or
a pharmaceutically acceptable salt thereof.
63 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
64 . A use of compound of claim 1 to prepare a medicament for treating or preventing a viral infection in a mammal.
65 . A use according to claim 64 wherein said viral infection is a herpes virus infection.
66 . A use according to claim 64 wherein said mammal is a human.
67 . A use according to claim 64 wherein said mammal is a livestock or companion animal.
68 . A use according to claim 66 wherein the infection is herpes simplex virus type 1, 2, 6, 7, or 8, varicella zoster virus, human cytomegalovirus, or Epstein-Barr virus.
69 . A use according to claim 66 wherein the infection is herpes simplex virus type 1 or 2, human herpes virus type 8, varicella zoster virus, human cytomegalovirus, or Epstein-Barr virus.
70 . A use according to claim 65 wherein the amount administered is from about 0.1 to about 300 mg/kg of body weight.
71 . A use according to claim 70 wherein the amount administered is from about 1 to about 30 mg/kg of body weight.
72 . A use according to claim 65 wherein the compound is administered parenterally, topically, intravaginally, orally, or rectally.
73 . A use for inhibiting a viral DNA polymerase, comprising contacting the polymerase with an effective inhibitory amount of a compound of claim 1 .
74 . A use of claim 73 wherein the polymerase and the compound are contacted in vitro.
75 . A use of claim 73 wherein the polymerase and the compound are contacted in vivo.
76 . A compound of claim 6 wherein G is C 1-4 alkyl substituted by NR 1 R 2 , R 6 is H, halo, or morpholinylmethyl, and R 7 is C 1-4 alkyl.
77 . A compound of claim 76 wherein G is morpholinylmethyl.
78 . A compound of claim 76 wherein R 4 and R 8 are hydrogen.
79 . A compound of claim 7 wherein R 5 , R 6 and R 8 are hydrogen.
80 . A compound of claim 79 wherein G is partially unsaturated C 2-4 alkyl substituted by hydroxy.
81 . A compound of claim 79 wherein R 7 is C 1-4 alkyl.
82 . A compound of claim 11 wherein R 4 and R 5 are hydrogen.
83 . A compound of claim 82 wherein R 7 is C 1-4 alkyl.
84 . A compound of claim 82 wherein G is partially unsaturated C 2-4 alkyl substituted by hydroxy.
85 . A compound of claim 15 wherein R 4 , R 5 and R 6 are hydrogen.
86 . A compound of claim 85 wherein G is partially unsaturated C 2-4 alkyl substituted by hydroxy.
87 . A compound of claim 25 wherein R 4 , and R 5 are hydrogen.
88 . A compound of claim 87 wherein G is partially unsaturated C 2-4 alkyl substituted by hydroxy, or C 1-4 alkyl substituted by NR 1 R 2 .
89 . A compound of claim 88 wherein G is morpholinylmethyl or hydroxypyrrolidinlyl.
90 . A compound of claim 88 wherein R 6 is H or morpholinylmethyl.
91 . A compound of claim 31 wherein R 4 , R 5 and R 6 are hydrogen, G is partially unsaturated C 2-4 alkyl substituted by hydroxy.
92 . A compound of claim 36 wherein R 4 , R 5 and R 6 are hydrogen, G is partially unsaturated C 2-4 alkyl substituted by hydroxy.
93 . A compound of claim 92 wherein R 7 is C 1-4 alkyl.
94 . A compound of claim 1 wherein W is W 14.4.
95 . A compound of claim 94 wherein R 4 , R 5 and R 6 are hydrogen, G is C 1-4 alkyl substituted by NR 1 R 2 .
96 . A compound of claim 95 wherein G is morpholinylmethyl.
97 . A compound of claim 95 wherein R 7 is C 1-4 alkyl.
98 . A compound of claim 39 wherein R 4 is hydrogen, G is partially unsaturated C 2-4 alkyl substituted by hydroxy.
99 . A compound of claim 98 wherein R 7 is C 1-4 alkyl.
100 . A compound of claim 44 wherein R 4 , R 6 and R 8 are hydrogen, G is C 1-4 alkyl substituted by NR 1 R 2 .
101 . A compound of claim 100 wherein G is morpholinylmethyl.
102 . A compound of claim 46 wherein R 4 , and R 8 are hydrogen, G is C 1-4 alkyl substituted by NR 1 R 2 .
103 . A compound of claim 102 wherein G is morpholinylmethyl.
104 . A compound of claim 47 wherein R 8 is hydroxy, G is C 1-4 alkyl substituted by NR 1 R 2 .
105 . A compound of claim 104 wherein G is morpholinylmethyl.
106 . A compound of claim 49 wherein R 8 is hydrogen, G is C 1-4 alkyl substituted by NR 1 R 2 .
107 . A compound of claim 106 wherein R 7 is C 1-4 alkyl.
108 . A compound of claim 106 wherein G is morpholinylmethyl.
109 . A compound of claim 50 wherein R 4 is hydrogen, G is C 1-4 alkyl substituted by NR 1 R 2
110 . A compound of claim 109 wherein G is morpholinylmethyl.
111 . A compound of claim 109 wherein R 7 is aryl.
112 . A compound of claim 53 wherein R 4 is hydrogen, G is partially unsaturated C 2-4 alkyl substituted by hydroxy.
113 . A compound of claim 112 wherein R 7 is C 1-4 alkyl.
114 . A compound of claims 76 - 113 wherein X is Cl.Cited by (0)
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