Patent EA-003945-B1 (EA)
Title: Quinolinecarboxamides as antiviral agents
Inventor: TURNER STEVEN RONALD
IPC: A61K31/554
Filed: 1999-12-22
Abstract: 1. A compound of formula I, or a pharmaceutically acceptable salt thereof wherein, X is a) O, or b) S; W is a) R<2>; b) NR<7>R<8>, c) OR<9>, or d) SOiR<9>. R<1> is a) Cl, b) F, c) Br, d) CN, or e) NO2; R<2> is a) (CH2CH2O)mR<10>, b) het, wherein said het is bonded via a carbon atom, c) C1-7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR<7>R<8>, R<11>, CN, SOiR<9> or OC2-4alkyl which is further substituted by het, OR<10>, OC (=O) aryl, or NR<7>R<8>, or d) C3-8 cycloalkyl, which may be partially unsaturated and is optionally substituted by R<11>, NR<7>R<8>, SOiR<9>, or C1-7 alkyl optionally substituted by R<11>, NR<7>R<8>, SOiR<9>; R<3> is a) H, b) halo, or c) C1-4 alkyl, optionally substituted by one to three halo; R<4> is a) H, b) aryl, c) het, d) SO2NHR<12>, e) CONHR<12>, f) NR<7>R<8>, g) NHCOR<12> h) NHSO2R<12> i) OC2-7 alkyl optionally substituted by-OH, j) SC2-7 alkyl optionally substituted by OH, or k) C1-8 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of N3, OR10, NR<7>R<8>, halo, SOiR<9>, OR<13> or R<11>; R<5> is a) H, b) halo, c) C [triple bond] CR<14>, d) NR<7>R<8>, e) SO2NHR<12>, f) het, or g) C1-7 alkyl, optionally substituted by OH; R<6> is a) H, b) halo, c) SC1-7 alkyl, e) C1-7 alkoxy, optionally substituted by one or more halo or OH, or f) C1-7 alkyl, which may be partially unsaturated and is optionally substituted by halo, NR<10> R<10>, (CH2)nOR<13>, R<11>, OC1-7 alkyl which is further substituted with het, NR<7>R<8>, or SOiR<9>; R<7> and R<8> 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 NR<10> R<10>, CONR<10>R<10>, R", SOiR<9>, halo; or d) R<7> and R<8> together with the nitrogen to which they are attached to form a het; R<9> is a) aryl, b) het, c) C3-8 cycloalkyl, or d) C1-7alkyl which may be partially unsaturated and optionally substituted by one or more OR<10>, O-aryl, het, aryl, NR<10> R<10>, CN, SH, SOiC1-6 alkyl, SOi aryl, halo, or CONR<10>R<10>; R<10> is a) H, or b) C1-7 alkyl, optionally substituted by OH; R<11> is a) OR<10>, b) O-het, c) O-aryl, d) CO2R<10>, e) het, f) aryl, or g) CN; R<12> is a) H, b) het, c) aryl, d) C3-8 cycloalkyl, or e) C1-7 alkyl optionally substituted by NR<7>R<8>, or R<11>; R<13> is a) (P=O)(OH)2, b) (P=O)(C1-7 alkoxy)2, c) CO(CH2)CON(CH3)(CH2)nS03<->M<+>, d) an amino acid, e) C(=O) aryl, f) C(=O) C1-6 alkyl, optionally substituted by NR<10> R<10>, or g) CO(CH2)nCO2H; R<14> is a) het, b) (CH2) nOR<13> or c) C1-7 alkyl substituted by one or more substituents selected from a group consisting of R, OC1-7 alkyl which is further substituted with het, NR<7>R<8>, or SOiR<9>; aryl is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic; 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 aryl is optionally substituted with one or more substituents selected from the group consisting of halo, OH, CF3, C1-6alkoxy, and C1-6 alkyl which maybe further substituted by one to three SR<10>, NR<10>R<10>, OR10, or CO2R<10>; wherein any het is optionally substituted with one or more substituents selected from the group consisting of halo, OH, CF3, C1-6alkoxy, oxo, oxine, and C1-6 alkyl which maybe further substituted by one to three SR<10>, NR<10> R<10>, OR<10>, or CO2R<10>; i is 0, 1, or 2; m is 1, 2, or 3; n is 1, 2, 3, 4, 5, or 6; and M is sodium, potassium, or lithium; with the proviso that R<1> is not Cl, Br, F, or CN; when X is O; R<2> is C1-7 alkyl optionally substituted by R<15>; R<3> is H, methyl, or halo; R<4> is H, CONH (C1-7alkyl), NR<16>R<17>, or C1-7 alkyl optionally substituted by OR<10>, CN, COOH, or NR<16>R<17>; R<5> is H, halo, SO2NHR<10>, NR<16>R<17>, or C1-7 alkyl optionally substituted by OR<10>; R<6> is H, halo, C1-7 alkoxy, or C1-7 alkyl optionally substituted by halo, OR', CO2R10 or NR<16>R<17>; R<15> is NR<16>R<17>, OR<10>, CN, or CO2R<10>; and R<16> and R<17> are independently H or C1-7 alkyl; or NR<16>R<17> together with the nitrogen to which they are attached form a 5-or 6-membered ring such as pyrrolidine, piperidine, morpholine, or piperazine. 2. A compound of claim 1 wherein R<1> is Cl. 3. A compound of claim 1 wherein R<1> is F. 4. A compound of claim 1 wherein R<1> is CN, or NO2; 5. A compound of claim 1 wherein R<2> is (CH2CH2O)mH, or (CH2CH2O)mC1-4 alkyl, wherein m is 2, or 3. 6. A compound of claim 1 wherein R<2> is C3-8 cycloalkyl optionally substituted by R<11>, NR<7>R<8>, SOiR<9>, or C1-7 alkyl optionally substituted by R<11>, NR<7>R<8>, or SOiR<9>; wherein R<7>, R<8>, R<9>, R<11> and i are the same as defined in claim 1. 7. A compound of claim 1 wherein R<2> is cyclopropyl. 8. A compound of claim 1 wherein R<2> is het wherein said het is bonded via a carbon atom and is the same as defined in claim 1. 9. A compound of claim 8 wherein het is tetrahydro-2H-pyranyl, piperidinyl, 1-methyl-piperidinyl, or 1,1-dioxo-tetrahydro-2H-thiopyran. 10. A compound of claim 1 wherein R<2> is C2-7 alkyl which is partially unsaturated and optionally substituted by NR<7>R<8>, R<11>, SOiR<9> or OC2-4 alkyl which is further substituted by het, OR<10>, or OC (=O) aryl; wherein R<7>, R<8>, R<9>, R<10> are the same as defined in claim 1. 11. A compound of claim 10 wherein R<2> is (Z or E)-CH=CHR<10>, or-C-C [triple bond] CR<10>; wherein said R<10> is H, or C1-7 alkyl optionally substituted by OH. 12. A compound of claim 1 wherein R<2> is C1-7 alkyl substituted by NR<7>R<8>, R<11>, SOiR<9>, or OC2-4 alkyl which is further substituted by het, OR<10> or OC (=O) aryl wherein R<7>, R<8>, R<9>, R<10> and R<11> are the same as defined in claim 1. 13. A compound of claim 1 wherein R<2> is C1-7 alkyl substituted by OC2-4 alkyl which is further substituted by het, OH, OC1-4 alkyl, or OC (=O) aryl. 14. A compound of claim 1 wherein R<2> is C1-7 alkyl substituted by SOiR<9> wherein R<9> and I are the same as defined in claim 1. 15. A compound of claim 1 wherein R<2> is C1-7 alkyl substituted by SOiR<9>, wherein R<9> is C1-4 alkyl, optionally substituted by OH, or R<9> is phenyl, optionally substituted by Cl; wherein i is 0, 1, or 2. 16. A compound of claim 1 wherein R<2> is methyl. 17. A compound of claim 1 wherein W is NR<7>R<8>, wherein R<7> and R<8> are the same as defined in claim 1. 18. A compound of claim I wherein W is NR<7>R<8>, wherein R<7> and R<8> together with the nitrogen to which they are attached to form a het, wherein said het is the same as defined in claim 1. 19. A compound of claim 18 wherein het is morpholine, piperidine, pyrrolidine, piperazine, or 4-methyl-piperazine. 20. A compound of claim 1 wherein W is NR<7>R<8>, wherein R<7> and R<8> are independently H or C1-4 alkyl optionally substituted by OH. 21. A compound of claim 18 wherein het is morpholine. 22. A compound of claim 1 wherein W is OR<9>, or SOiR<9> wherein R<9> is C1-6alkyl which may be partially unsaturated and optionally substituted by OR<10>, O-aryl, het, aryl, NR<10>R<10>, CN, CONR<10> R<10> or halo; wherein R<10> is H or C1-4 alkyl. 23. A compound of claim 1 wherein R<3> is H. 24. A compound of claim 1 wherein R<3> is CF3, or halo. 25. A compound of claim 1 wherein R<4> is aryl or het. 26. A compound of claim 1 wherein R<4> is SO2NHR<12>, CONHR<12>, NHCOR<12> or NHSO2R<12>, wherein R<12> is the same as defined in claim 1. 27. A compound of claim I wherein R<4> is C2-8 alkyl which is partially unsaturated and optionally substituted by OR<10>, NR<7>R<8>, halo, SOiR<9>, OR<13> or R<11>, wherein R<7>, R<8>, R<9>, R<10>, R<11> and R<13> are the same as defined in claim 1. 28. A compound of claim 1 wherein R<4> is (Z or E)-CH=CHC1-4 alkyl, optionally substituted by OH. 29. A compound of claim 1 wherein R<4> is -C [triple bond] CC1-4 alkyl, optionally substituted by OH or OR<13>, wherein R<13> is (P=O) (OH)2, (P=O)(C1-7 alkoxy)2, or CO (CH2) 6CON (CH3) (CH2) nSO3<->M<+>. 30. A compound of claim I wherein R<4> is C1-8 alkyl substituted by OR<13> wherein R<13> is (P=O) (OH) 2, (P=O) (C1-7 alkoxy) 2, or CO (CH2) nCON (CH3) (CH2)6SO3<->M<+.> 31. A compound of claim 1 wherein R<4> is C1-8 alkyl substituted by SOiR<9>, wherein R<9> is the same as defined in claim 1. 32. A compound of claim 1 wherein R<4> is NR<7>R<8>, wherein R<7> and R<8> are the same as defined in claim 1. 33. A compound of claim 1 wherein R<4> is C1-8alkyl substituted by NR<7>R<8>, wherein R<7> and R<8> are the same as defined in claim 1. 34. A compound of claim 33 wherein R<7> and R<8> together with the nitrogen to which they are attached to form a het, wherein het is the same as defined in claim 1. 35. A compound of claim 33 wherein R<7> and R<8> are independently C1-6 alkyl, optionally substituted by one or more substituents selected from a group consisting of OH, aryl, or CN wherein aryl is the same as defined in claim 1. 36. A compound of claim 1, wherein R<4> is C1-8 alkyl substituted by N3. 37. A compound of claim 1, wherein R<4> is C1-8 alkyl substituted by het wherein het is the same as defined in claim 1. 38. A compound of claim 1, wherein R<4> is 4-morpholine methyl. 39. A compound of claim 1, wherein R<4> is C1-7 alkyl substituted by R<11>, wherein R<11> is the same as defined in claim 1. 40. A compound of claim 1, wherein R<5> is H or C1-7 alkyl optionally substituted by OH. 41. A compound of claim 1, wherein R<6> is OC1-7 alkyl optionally substituted by one or more OH. 42. A compound of claim 1, wherein R<6> is halo. 43. A compound of claim 1, wherein R<6> is C [triple bond] CC1-7 alkyl substituted by one or more OH, or C2-7 alkoxy s