Patent EA-003607-B1 (EA)
Title: 4-OXO-4,7-DIHYDRO-THIENO[2,3-b]PYRIDINE-5-CARBOXAMIDES AS ANTIVIRAL AGENTS
Inventor: SCHUTE MARK E
IPC: A61K31/5377
Filed: 2000-03-07
Abstract: 1. A compound of formula I: or a pharmaceutically acceptable salt thereof wherein R<1> is (a) Cl, (b) Br, or (c) F; R<2> is (a) H or (b) R<5>; R<3> is (a) H, (b) halo, S(O)2R<6>, (d) (C=O)R<6>, (e)(C=O)OR<9>, (f) cyano or (g) C1-7alkyl which may be partially unsaturated and optionally substituted by one or more substituents of the group R<11>, OR<13> or NR<7>R<8>; R<4> is H; R<5> is C1-7alkyl which may be partially unsaturated and optionally substituted by one or more substituents of the group R<11> and NR<7>R<8>; R<6> is NR<7>R<8>; R<7> and R<8> are independently (a) H, (b) is C1-7alkyl which may be substituted by one or more substituents of the group R<11>, or (c) R<7> and R<8> together with a nitrogen atom to which they are attached form morpholino, pyrrolidino or thiomorpholino; R<9> is C1-7alkyl; R<10> is H or C1-7 alkyl; R<11> is (a) OR<10>, (b) CO2R<10>, (c) morpholino, thiomorpholino, tetrahydrofuryl, pyridine or pyrrolidino, or (d) phenyl; R<13> is (a) C(=O) phenyl or (b) C(=O)C1-7alkyl optionally substituted by NR<7>R<8> or CO2H; wherein any phenyl is optionally substituted by one or more substituents of the group OH and C1-7alkyl, which may be further substituted by morpholino. 2. The compound of claim 1 wherein R<1> Cl. 3. The compound of any one of claims 1-2 wherein R<2> is H. 4. The compound of any one of claims 1-2 wherein R<2> is R<5>. 5. The compound of claim 4 wherein R<5> is C1-7alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from phenyl, morpholino, pyrrolidino or thiomorpholino. 6. The compound of claim 5 wherein R<5> is C1-7 alkyl. 7. The compound of claim 1 wherein R<2> is methyl, ethyl, propyl, isopropyl, butyl, tertbutyl, carboxymethyl, (C1-7alkoxy)carbonylmethyl, 2-hydroxyethyl, 2-(diethylamino) ethyl, benzyl, , 3-fluorobenzyl, 3-phenylpropyl, 2-tetrahydrofuranylmethyl, 2-pyrrolidinoethyl, 3-pyridylmethyl or carboxymethyl. 8. The compound of claim 1 wherein R<2> is methyl, ethyl, isopropyl, 2-hydroxyethyl, 2-(diethylamino)ethyl, or 2-(dimethylamino)ethyl. 9. The compound of claim 1 wherein R<3> is H, halo or C1-7alkyl, which may be partially unsaturated and optionally substituted by one or more substituents of the group R<11>, OR<13> or NR<7>R<8>. 10. The compound of claim 1 wherein R<3> is C1-7alkyl which may be partially unsaturated and is optionally substituted by one or more substituents of the group R<11>, OR<13> or NR<7>R<8>. 11. The compound of claim 1 wherein R<3> is C1-7 alkyl which may be partially unsaturated and is substituted by one or more substituents of the group R<11> and OR<13>. 12. The compound of claim 1 wherein R<3> is bromo, iodo, 3-hydroxy-1-propynyl, 3-methoxy-1-propynyl, 4-hydroxy-1-butynyl, 3-hydroxypropyl, cyano, 4,4-di (methoxycarbonyl)-1-butynyl, 4-hydroxybutyl, 3-(3-carboxypropanoyloxy)-1-propynyl, 3-(morpholinoacetoxy)-1-propynyl, 3-(2-amino-3-methylbutanoyloxy)-1-propynyl, thiomorpholinomethyl, N-[2-(4-hydroxyphenyl)-2-hydroxyethyl]-N-(methyl) aminomethyl, morpholinocarbonyl, 3-[3-(morpholinomethyl)benzoyloxy]-1-propynyl, hydroxymethyl, metoxycarbonyl, morpholinosulfonyl, morpholinomethyl or N-(2-phenyl-2-hydroxyethyl)-N-methylaminomethyl. 13. The compound of claim 1 wherein R<3> is iodo, 3-hydroxy-1-propynyl, 4-hydroxy-1-butynyl, 3-hydroxypropyl, morpholinomethyl, N-[2-(4-hydroxyphenyl)-2-hydroxyethyl]-N-(methyl) aminomethyl or 4-hydroxybutyl. 14. The compound of claim 1 wherein R<3> is 3-hydroxy-1-propynyl, morpholinomethyl, N-[2-(4-hydroxyphenyl)-2-hydroxyethyl]-N-(methyl)aminomethyl or 3-hydroxypropyl. 15. The compound of claim 1 which is: (1) N-(4-Chlorobenzyl)-4-hydroxythieno [2,3-b]pyridine-5-carboxamide; (2) N-(4-Chlorobenzyl)-4-hydroxy-2-iodothieno [2,3-b]pyridine-5-carboxamide; (3) N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylsulfonyl)thieno[2,3-b]pyridine-5-carboxamide; (4) 2-Bromo-N-(4-chlorobenzyl)-4-hydroxythieno[2,3-b]pyridine-5-carboxamide; (5) N-(4-Chlorobenzyl)-4-hydroxy-2-(3-hydroxy-1-propynyl)thieno[2,3-b]pyridine-5-carboxamide; (6) N-(4-Chlorobenzyl)-4-hydroxy-2-(3-methoxy-1-propynyl)thieno[2,3-b]pyridine-5-carboxamide; (7) N-(4-Chlorobenzyl)-4-hydroxy-2-(4-hydroxy-1-butynyl)thieno[2,3-b]-pyridine-5-carboxamide; (8) N-(4-Chlorobenzyl)-4-hydroxy-2-(3-hydroxypropyl)thieno[2,3-b]pyridine-5carboxamide; (9) N-(4-Chlorobenzyl)-2-cyano-4-hydroxythieno[2,3-b]pyridine-5-carboxamide; (10) Dimethyl 2-[3-(5-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxythieno[2,3-b]pyridin-2-yl)-2-propynyl]malonate; (11) 2-Bromo-N-(4-chlorobenzyl)-7-ethyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (12) N-(4-Chlorobenzyl)-7-ethyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5carboxamide; (13) N-(4-Chlorobenzyl)-7-ethyl-2-iodo-4-oxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carboxamide; (14) N-(4-Chlorobenzyl)-7-ethyl-2-(3-hydroxy-1-propynyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (15) N-(4-Chlorobenzyl)-7-ethyl-2-(4-hydroxy-1-butynyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (16) N-(4-Chlorobenzyl)-7-ethyl-2-(3-hydroxypropyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (17) N-(4-Chlorobenzyl)-7-(2-hydroxyethyl)-2-(3-hydroxy-1-propynyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (18) N-(4-Chlorobenzyl)-7-[2-(diethylamino)ethyl]-2-(3-hydroxy-1-propynyl)-4oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (19) 2-[5-{[(4-Chlorobenzyl)amino]carbonyl}-2-(3-hydroxy-1-propynyl)-4-oxothieno[2,3-b]pyridin-7(4H)-yl]acetic acid; (20) N-(4-Chlorobenzyl)-7-ethyl-2-(4-hydroxybutyl)-4-oxo-4,7dihydrothieno[2,3-b]pyridine-5-carboxamide; (21) N-(4-Chlorobenzyl)-7-(2-hydroxyethyl)-2-(3-hydroxypropyl)-4-oxo-4,7dihydrothieno [2,3-b]pyridine-5-carboxamide; (22) N-(4-Chlorobenzyl)-7-[2-(diethylamino)ethyl]-2-(3-hydroxypropyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (23) N-(4-Chlorobenzyl)-2-iodo-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (24) N-(4-Chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (25) N-(4-Chlorobenzyl)-2-(3-hydroxypropyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (26) N-(4-Chlorobenzyl)-2-iodo-7-isopropyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (27) N-(4-Chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-isopropyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (28) N-(4-Chlorobenzyl)-2-(3-hydroxypropyl)-7-isopropyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (29) 4-{[3-(5-{[(4-Chlorobenzyl)amino]carbonyl}-7-ethyl-4-oxo-4,7dihydrothieno[2,3-b]pyridin-2-yl)-2-propynyl]oxy}-4-oxobutanoic acid; (30) 3-(5-{[(4-Chlorobenzyl)amino]carbonyl}-7-ethyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)-2-propynyl-2-(4-morpholinyl)acetate; (31) 3-(5-{[(4-Chlorobenzyl)amino]carbonyl}-7-ethyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)-2-propynyl-2-amino-3-methylbutanoate; (32) 3-(5-{[(4-Chlorobenzyl)amino]carbonyl}-7-ethyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)-2-propynyl-3-(4-morpholinylmethyl)benzoate; (33) Methyl-5-{[4-chlorobenzyl)amino]carbonyl}-4-hydroxythienol[2,3b]pyridine-2-carboxylate; (34) N-(4-Chlorobenzyl)-4-hydroxy-2-(hydroxymethyl)thieno[2,3-b]pyridine-5carboxamide; (35) N-(4-chlorobenzyl)-2-(hydroxymethyl)-7-methyl-4-oxo-4,7-dihydrothienol[2,3-b]pyridine-5-carboxamide; (36) N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinyhnethyl)-4-oxo-4,7-dihydrothienol[2,3-b]pyridine-5-carboxamide; (37) N-(4-chlorobenzyl)-7-methyl-4-oxo-2-(4-thiomorpholinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (38) N-(4-chlorobenzyl)-2-(((2-hydroxy-2-(4-hydroxyphenyl)ethyl)(methyl)amino)methyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (39) N-(4-chlorobenzyl)-2-(((2-hydroxy-2-phenylethyl)(methyl)amino)methyl)-7methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (40) N-(4-chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide; (41) N-(4-Chlorobenzyl)-7-ethyl-2-(4-morpholinylmethyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (42) N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-oxo-7-propyl-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (43) N-(4-Chlorobenzyl)-7-isopropyl-2-(4-morpholinylmethyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (44) N-(4-Fluorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (45) N-(4-bromobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (46) N-(4-chlorobenzyl)-4-hydroxy-2-(4-morpholinylcarbonyl)thieno[2,3-b]pyridine-5-carboxamide; (47) N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylcarbonyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (48) 7-Benzyl-N-(4-chlorobenzyl)-2-(4-morpholinylmethyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (49) N-(4-Chlorobenzyl)-7-(3-fluorobenzyl)-2-(4-morpholinylmethyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (50) N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-oxo-7-(3-phenylpropyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (51) N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-oxo-7-(tetrahydro-2-furanylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (52) N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-oxo-7-[2-(1-pyrrolidinyl)ethyl]-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (53) N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-oxo-7-(3-pyridinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (54) N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-oxo-7-(4-pyridinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; or a pharmaceutically acceptable salt thereof. 16. The compound of claim 1 which is: (1) N-(4-Chlorobenzyl)-7-ethyl-2-(3-hydroxy-1-propynyl)-4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxamide; (2) N-(4-Chlorobenzyl)-7-ethyl-2-(4-hydroxy-1-butynyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide; (3) N-(4-Chlorobenzyl)-7-ethyl-2-(3-hydroxypropyl)-4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxamide; (4) N-(4-Chlorobenzyl)-7-(2-hydroxyethyl)-2-(3-hydroxy-1-propynyl)-4-oxo