Claims for Patent: 7,671,032

Summary for Patent: 7,671,032

Title:	HCV NS-3 serine protease inhibitors
Abstract:	Peptidomimetic compounds are described which inhibit the NS3 protease of the hepatitis C virus (HCV). The compounds have the formula where the variable definitions are as provided in the specification. The compounds comprise a carbocyclic P2 unit in conjunction with a novel linkage to those portions of the inhibitor more distal to the nominal cleavage site of the native substrate, which linkage reverses the orientation of peptidic bonds on the distal side relative to those proximal to the cleavage site. ##STR00001##
Inventor(s):	Rosenquist; Asa (Huddinge, SE), Thorstensson; Fredrik (Linkoping, SE), Johansson; Per-Ola (Linkoping, SE), Kvarnstrom; Ingemar (Linkoping, SE), Samuelsson; Bertil (Huddinge, SE), Wallberg; Hans (Huddinge, SE)
Assignee:	Medivir AB (Huddinge, SE)
Application Number:	10/572,349
Patent Claims:	1. A compound of formula VI: ##STR00162## wherein A is C(.dbd.O)OR.sup.1, or C(.dbd.O)NHSO.sub.2R.sup.2, wherein; R.sup.1 is hydrogen, or C.sub.1-C.sub.6alkyl; R.sup.2 is C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl; wherein R.sup.2 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl, NH.sub.2C(.dbd.O)--, Y--NRaRb, Y--O--Rb, Y--C(.dbd.O)Rb, Y--(C.dbd.O)NRaRb, Y--NRaC(.dbd.O)Rb, Y--NHSO.sub.pRb, Y--S(.dbd.O).sub.pRb, Y--S(O)NRaRb, Y--C(.dbd.O)ORb and Y--NRaC(O)ORb; Y is independently a bond or C.sub.1-C.sub.3alkylene; Ra is independently H or C.sub.1-C.sub.3alkyl; Rb is independently H, C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl or C.sub.0-C.sub.3alkylheterocyclyl; p is independently 1 or 2; M is CR.sup.7R.sup.7'; R.sup.7' taken together with R.sup.7 forms a C.sub.3C.sub.6cycloalkyl ring substituted with J; q' is 0 and k is 1; Rz is H, or together with the asterisked carbon forms an olefinic bond; Rq is H or C.sub.1-C.sub.6alkyl; W is --O-- or --S--; R.sup.8 is a ring system containing 1 or 2 saturated, partially saturated or unsaturated rings each of which has 4-7 ring atoms and each of which has 0 to 4 hetero atoms selected from S, O and N, the ring system being optionally spaced from W by a C.sub.1-C.sub.3alkyl group; any of which R8 groups can be optionally mono, di, or tri substituted with R.sup.9, wherein R.sup.9 is independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl, NH.sub.2C(.dbd.O)--, Y--NRaRb, Y--O--Rb, Y--C(.dbd.O)Rb, Y--(C.dbd.O)NRaRb, Y--NRaC(O)Rb, Y--NHSO.sub.pRb, Y--S(.dbd.O).sub.pRb, Y--S(.dbd.O).sub.pNRaRb, Y--C(.dbd.O)ORb and Y--NRaC(O)ORb; wherein said carbocyclyl or heterocyclyl moiety is optionally substituted with R.sup.10; wherein R.sup.10 is C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkoxy, amino, sulfonyl, (C.sub.1-C.sub.3 alkyl)sulfonyl, NO.sub.2, OH, SH, halo, haloalkyl, carboxyl, amido; J is a single 3 to 10-membered saturated or partially unsaturated alkylene chain that extends from the R.sup.7/R.sup.7' cycloalkyl to G and forms a macrocycle, which chain is optionally interrupted by one to three heteroatoms independently selected from: --O--, --S-- or --NR.sup.12--, and wherein 0 to 3 carbon atoms in the chain are optionally substituted with R.sup.14; wherein; R.sup.12 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6cycloalkyl, or COR.sup.13; R.sup.13 is C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl; R.sup.14 is independently selected from H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, hydroxyl, halo, amino, oxo, thio, or C.sub.1-C.sub.6 thioalkyl; m is 0; n is 0; G is --NRy-, or --NRjNRj-; Ry is J; one Rj is H and the other Rj is J; R.sup.16 is H; or R.sup.16 is C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl, any of which can be substituted with halo, oxo, nitrile, azido, nitro, C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl, NH.sub.2CO--, Y--NRaRb, Y--O--Rb, Y--C(O)Rb, Y--(C.dbd.O)NRaRb, Y--NRaC(.dbd.O)Rb, Y--NHSO.sub.pRb, Y--S(.dbd.O).sub.pRb, Y--S(.dbd.O).sub.pNRaRb, Y--C(O)ORb, Y--NRaC(O)ORb; or a pharmaceutically acceptable salt or thereof. 2. A compound according to claim 1, with the partial structure: ##STR00163## 3. A compound according to claim 1, with the partial structure ##STR00164## 4. A compound according to claim 3, wherein Rq is C.sub.1-C.sub.3 alkyl. 5. A compound according to claim 1, wherein R.sup.16H, C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.6cycloalkyl. 6. A compound according to claim 1, wherein W is --O--. 7. A compound according to claim 6 wherein R.sup.8 is optionally substituted C.sub.0-C.sub.3alkylcarbocyclyl or optionally substituted C.sub.0-C.sub.3alkylheterocyclyl. 8. A compound according to claim 7, wherein the C.sub.0-C.sub.3 alkyl moiety is methylene. 9. A compound of formula VI: ##STR00165## wherein A is C(.dbd.O)NHSO.sub.2R.sup.2, or C(.dbd.O)OR.sup.1 wherein; R.sup.1 is H or C.sub.1-C.sub.6alkyl; R.sup.7 is C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl; wherein R.sup.2, is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl, NH.sub.2C(.dbd.O)--, Y--NRaRb, Y--O--Rb, Y--C(.dbd.O)Rb, Y--(C.dbd.O)NRaRb, Y--NRaC(.dbd.O)Rb, Y--NHSO.sub.pRb, Y--S(.dbd.O)Rb, Y--S(.dbd.O).sub.pNRaRb, Y--C(.dbd.O)ORb and Y--NRaC(.dbd.O)ORb; Y is independently a bond or C.sub.1-C.sub.3alkylene; Ra is independently H or C.sub.1-C.sub.3alkyl; Rb is independently H, C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl or C.sub.0-C.sub.3alkylheterocyclyl; p is independently 1 or 2; M is CR.sup.7R.sup.7'; R.sup.7' taken together with R.sup.7 forms a C.sub.3-C.sub.6cycloalkyl ring substituted with J; q' is 0 and k is 1; Rz is H or together with the asterisked carbon forms an olefinic bond; Rq is H or C.sub.1-C.sub.6 alkyl; W is --O--, or --S--; J is a single 3 to 10-membered saturated or partially unsaturated alkylene chain that extends from the R.sup.7/R.sup.7' cycloalkyl to G and forms a macrocycle, which chain is optionally interrupted by one to three heteroatoms independently selected from: --O--, --S-- or NR.sup.12--, and wherein 0 to 3 carbon atoms in the chain are optionally substituted with R.sup.14; wherein; R.sup.12 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6cycloalkyl, or COR.sup.13; R.sup.13 is C.sub.1-C.sub.6 alkyl, C.sub.0-C.sub.3alkylcycloalkyl, or C.sub.0-C.sub.3alkylheterocyclyl; R.sup.14 independently selected from H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, hydroxy, halo, amino, oxo, thio, or C.sub.1-C.sub.6 thioalkyl; m is 0: n is 0; G is --NRy- or --NRjNRj-; Ry is J; one Rj is H and the other Rj is H or J; R.sup.16 is H; or R.sup.16 is C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl, any of which can be substituted with halo, oxo, nitrile, azido, nitro, C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl, NH.sub.2CO--, Y--NRaRb, Y--O--Rb, Y--C(.dbd.O)Rb, Y--(C.dbd.O)NRaRb, Y--NRaC(.dbd.O)Rb, Y--NHSO.sub.pRb, Y--S(.dbd.O)Rb, Y--S(.dbd.O).sub.pNRaRb, Y--C(O)ORb, Y--NRaC(O)ORb; wherein R.sup.8 is C.sub.0-C.sub.3alkylaryl, or C.sub.0-C.sub.3alkylheteroaryl, either of which is optionally mono, di, or tri substituted with R.sup.9, wherein; R.sup.9 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkoxy, NO.sub.2, OH, halo, trifluoromethyl, amino or amido optionally mono- or di-substituted with C.sub.1-C.sub.6alkyl, carboxy, C.sub.0-C.sub.3alkylaryl, or C.sub.0-C.sub.3alkylheteroaryl, the aryl or heteroaryl being optionally substituted with R.sup.10; wherein R.sup.10 is C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkoxy, amino optionally mono- or di-substituted with C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3 alkyl amide, sulfonylC.sub.1-C.sub.3alkyl, NO.sub.2, OH, halo, trifluoromethyl, carboxyl, or heteroaryl or a pharmaceutically acceptable salt thereof. 10. A compound according to claim 9 wherein R.sup.9 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkoxy, amino, di-(C.sub.1-C.sub.3 alkyl)amino, C.sub.1-C.sub.3alkylamide, aryl or heteroaryl, the aryl or heteroaryl being optionally substituted with R.sup.10; wherein R.sup.10 is C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkoxy, amino, mono- or di-C.sub.1-C.sub.3 alkylamino, amido, C.sub.1-C.sub.3 alkylamide, halo, trifluoromethyl, or heteroaryl. 11. A compound according to claim 10, wherein, R.sup.10 is C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, amino optionally mono- or di-substituted with C.sub.1-C.sub.3 alkyl, amido, C.sub.1-C.sub.3-alkylamide, halo, or heteroaryl. 12. A compound according to claim 10 wherein R.sup.10 is methyl, ethyl, isopropyl, tert-butyl, methoxy, chloro, amino optionally mono- or di substituted with C.sub.1-C.sub.3 alkyl, amido, C.sub.1-C.sub.3alkylamide, or C.sub.1-C.sub.3alkyl thiazolyl. 13. A compound according to claim 8, wherein R.sup.8 is 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 1-naphthyl, 2-napthyl, or quinolinyl any of which is unsubstituted, mono, or disubstituted with R.sup.9 as defined. 14. A compound according to claim 13 wherein R.sup.8 is 1-naphthylmethyl, or quinolinyl any of which is unsubstituted, mono, or disubstituted with R.sup.9 as defined. 15. A compound according to claim 14 wherein R.sup.8 is: ##STR00166## wherein R.sup.9a is C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.6alkoxy; thioC.sub.1-C.sub.3alkyl; amino optionally substituted with C.sub.1-C.sub.6alkyl; C.sub.0-C.sub.3alkylaryl; or C.sub.0-C.sub.3alkylheteroaryl, C.sub.0-C.sub.3alkylheterocyclyl, said aryl, heteroaryl or heterocycle being optionally substituted with R.sup.10 wherein R.sup.10 is C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkyl, C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkoxy, amino optionally mono- or di-substituted with C.sub.1-C.sub.6alkyl, amido, C.sub.1-C.sub.3alkyl amide; and R.sup.9b is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6-alkoxy, amino, di(C.sub.1-C.sub.3alkyl)amino, (C.sub.1-C.sub.3alkyl) amide, NO.sub.2, OH, halo, trifluoromethyl, carboxyl. 16. A compound according to claim 15, wherein R.sup.9a is aryl or heteroaryl, either of which is optionally substituted with R.sup.10 as defined. 17. A compound according to 16, wherein R.sup.9a is selected from the group consisting of: ##STR00167## wherein R.sup.10 is H, C.sub.1-C.sub.6alkyl, or C.sub.0-C.sub.3alkylcycloalkyl, amino optionally mono- or di-substituted with C.sub.1-C.sub.6alkyl, amido, (C.sub.1-C.sub.3alkyl)amide. 18. A compound according to claim 16, wherein R.sup.9a is optionally substituted phenyl, preferably phenyl substituted with C.sub.1-C.sub.6alkyl; C.sub.1-C.sub.6alkoxy; or halo. 19. A compound according to claim 15, wherein R.sup.8 is: ##STR00168## wherein R.sup.10a is H, C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, amino optionally mono- or di-substituted with C.sub.1-C.sub.6alkyl, amido, (C.sub.1-C.sub.3 alkyl)amide, heteroaryl or heterocyclyl; and R.sup.9b is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6-alkoxy, amino, di(C.sub.1-C.sub.3 alkyl)amino, (C.sub.1-C.sub.3 alkyl)amide, NO.sub.2, OH, halo, trifluoromethyl, or carboxyl. 20. A compound according to any claim 15, wherein R.sup.9b is C.sub.1-C.sub.6-alkoxy, preferably methoxy. 21. A compound according to claim 1, wherein R.sup.2 is optionally substituted C.sub.1-C.sub.6 alkyl. 22. A compound according to claim 21, wherein R.sup.2 is methyl. 23. A compound according to claim 1, wherein R.sup.2 is optionally substituted C.sub.3-C.sub.7cycloalkyl. 24. A compound according to claim 1, wherein R.sup.2 is optionally substituted C.sub.0-C.sub.6alkylaryl. 25. A compound according to claim 1, wherein A is C(.dbd.O)OR.sup.1 wherein R.sup.1 is H. 26. A compound according to claim 1 wherein A is C(.dbd.O)OR.sup.1, wherein R.sup.1 is H or C.sub.1-C.sub.6 alkyl. 27. A compound according to claim 1, wherein R.sup.7 and R.sup.7' together define a spiro-cyclopropyl or spiro-cyclobutyl ring. 28. A compound according to claim 1, wherein J is a 3 to 8-membered saturated or unsaturated alkylene chain optionally containing one to two heteroatoms independently selected from: --O--, --S-- or --NR.sup.12--, wherein R.sup.12 is H, C.sub.1-C.sub.6 alkyl, or --C(.dbd.O)C.sub.1-C.sub.6 alkyl. 29. A compound according to claim 28, wherein J is a 4 to 7-membered saturated or unsaturated, all carbon alkylene chain. 30. A compound according to claim 28, wherein J is saturated or mono-unsaturated. 31. A compound according to claim 28, wherein J is dimensioned to provide a macrocycle of 14 or 15 ring atoms. 32. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefore. 33. A pharmaceutical composition according to claim 32, further comprising an additional HCV antiviral, selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin and interferon. 34. A compound according to claim 3 wherein Rq is methyl. 35. A compound according to claim 5, wherein R.sup.16 is H or methyl. 36. A compound according to claim 23, wherein R.sup.2 is cyclopropyl. 37. A compound according to claim 9, with the partial structure: ##STR00169## 38. A compound according to claim 9, with the partial structure ##STR00170## 39. A compound according to claim 38, wherein Rq is C.sub.1-C.sub.3 alkyl. 40. A compound according to claim 39, wherein Rq is methyl. 41. A compound according to claim 9, wherein W is --O--. 42. A compound according to claim 9, wherein the C.sub.0-C.sub.3 alkyl moiety of R.sup.9 is a bond. 43. A compound according to claim 9, wherein R.sup.16 is H or methyl. 44. A compound according to claim 9, wherein R.sup.2 is optionally substituted C.sub.3-C.sub.7cycloalkyl. 45. A compound according to claim 44, wherein R.sup.2 is cyclopropyl. 46. A compound according to claim 9, wherein J is a 3 to 8-membered saturated or unsaturated alkylene chain optionally containing one to two heteroatoms independently selected from: --O--, --S-- or --NR.sup.12--, wherein R.sup.12 is H, or C.sub.1-C.sub.6 alkyl. 47. A compound according to claim 46, wherein J is a 4 to 7-membered saturated or unsaturated, all carbon alkylene chain. 48. A compound according to claim 46, wherein J is saturated or mono-unsaturated. 49. A compound according to claim 46, wherein J is dimensioned to provide a macrocycle of 14 or 15 ring atoms. 50. A compound according to claim 9 wherein A is C(O)NHSO.sub.2R.sup.2; R.sup.2 is C.sub.0-C.sub.3alkylcarbocyclyl; Rz is H; Rq is H; W is --O--; J is a single 4 to 7-membered mono-unsaturated alkylene chain that extends from the R.sup.7/R.sup.4' cycloalkyl to G and forms a macrocycle; G is --NRy-; Ry is J; R.sup.16 is C.sub.1-C.sub.6alkyl; R.sup.8 is heteroaryl, which is optionally mono, di, or tri substituted with R.sup.9, wherein; R.sup.9 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkoxy, or heteroaryl, the heteroaryl being optionally substituted with R.sup.10; wherein R.sup.10 is C.sub.1-C.sub.6alkyl. 51. A compound according to claim 9 wherein R.sup.2 is cyclopropyl; Rz is H; Rq is H; W is --O--; and J is a single mono-unsaturated alkylene chain that extends from the R.sup.7/R.sup.7' cyclopropyl to G and forms a macrocycle dimensioned to provide a macrocycle of 14 or 15 ring atoms. 52. A pharmaceutical composition comprising a compound as defined in claim 9 and a pharmaceutically acceptable carrier therefor. 53. A pharmaceutical composition according to claim 9, further comprising an additional HCV antiviral, selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin and interferon. 54. A compound selected from the group consisting of: (Z)-(1R,4R,6S,16R,18R)-14-tert-Butoxycarbonylamino-18-(7-methoxy-2-phenyl- -quinolin-4-yloxy)-2,15-dioxo-3,14-diaza-tricyclo[14.3.0.0..sup.4.6]nonade- c-7-ene-4-carboxylic acid ethyl ester; (Z)-(1R,4R,6S,16R,18R)-14-tert-Butoxycarbonylamino-18-(7-methoxy-2-phenyl- -quinolin-4-yloxy)-2,15-dioxo-3,14-diaza-tricyclo[14.3.0.0..sup.4.6]nonade- c-7-ene-4-carboxylic acid; 17-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13-diaza-tricyclo[1- 3.3.0.0*4,6*]octadec-7-ene-4-carboxylic acid ethyl ester; 17-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13-diaza-tricyclo[1- 3.3.0.0*4,6*]octadec-7-ene-4-carboxylic acid; Cyclopropanesulphonic acid [17-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13-diaza-tricyclo[- 13.3.0.0*4,6*octadec-7-ene-4-carbonyl]-amide; 17-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-13-methyl-2,14-dioxo-3,13-diaza-- tricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carboxylic acid ethyl ester; 17-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-13-methyl-2,14-dioxo-3,13-diaza-- tricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carboxylic acid ethyl ester; Cyclopropanesulphonic acid [17-(7-methoxy-2-phenyl-quinolin-4-yloxy)-13-methyl-2,14-dioxo-3,13-diaza- -tricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carboxylic acid ethyl ester; [4-Cyclopropanesulphonylaminocarbonyl-17-(7-methoxy-phenyl-quinolin-4-ylo- xy)-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4,6*]octadec-7-en-13-yl]-carba- mic acid tert.butyl ester; Cyclopropanesulphonic acid[13-amino-17-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13-di- aza-tricyclo[13.3 trifluoroacetic acid salt; Cyclopropanesulphonic acid {17-[2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-13-methyl-2,1- 4-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carbonyl)-amide; N-{4-[4-(4-Cyclopropanesulphonylaminocarbonyl-13-methyl-2,14-dioxo-3,13-d- iaza-tricyclo[13.3.0.0*4,6]octadec-7-en-17-yloxy)-7-methoxy-quinoli-2-yl]-- thiazol-2-yl}-3,3-dimethylbutyramide; 17-[2-(2-Isopropylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-13-meth- yl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carboxylic acid ethyl ester; 17-[2-(2-Isopropylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-13-meth- yl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carboxylic acid; and Cyclopropanesulphonic acid {17-[2-(2-isopropylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-13-met- hyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carbonyl}- -amide or a pharmaceutically acceptable salt thereof. 55. A pharmaceutical composition comprising a compound as defined in claim 54, and a pharmaceutically acceptable carrier therefor. 56. A compound according to claim 1, wherein R.sup.2 is optionally substituted phenyl. 57. A compound according to claim 1, wherein A is C(.dbd.O)OR.sup.1, wherein R.sup.1 is methyl, ethyl, or tert-butyl.