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.
Inventor(s):	Asa Rosenquist, Fredrik Thorstensson, Per-Ola Johansson, Ingemar Kvarnstrom, Bertil Samuelsson, Hans Wallberg
Assignee:	Medivir AB
Application Number:	US10/572,349
Patent Claims:	1. A compound of formula VI: wherein A is C(═O)OR1, or C(═O)NHSO2R2, wherein; R1 is hydrogen, or C1-C6alkyl; R2 is C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl; wherein R2 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, NH2C(═O)—, Y—NRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSOpRb, Y—S(═O)pRb, Y—S(O)NRaRb, Y—C(═O)ORb and Y—NRaC(O)ORb; Y is independently a bond or C1-C3alkylene; Ra is independently H or C1-C3alkyl; Rb is independently H, C1-C6alkyl, C0-C3alkylcarbocyclyl or C0-C3alkylheterocyclyl; p is independently 1 or 2; M is CR7R7′; R7′ taken together with R7 forms a C3C6cycloalkyl 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 C1-C6alkyl; W is —O— or —S—; R8 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 C1-C3alkyl group; any of which R8 groups can be optionally mono, di, or tri substituted with R9, wherein R9 is independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, NH2C(═O)—, Y—NRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(O)Rb, Y—NHSOpRb, Y—S(═O)pRb, Y—S(═O)pNRaRb, Y—C(═O)ORb and Y—NRaC(O)ORb; wherein said carbocyclyl or heterocyclyl moiety is optionally substituted with R10; wherein R10 is C1-C6alkyl, C3-C7cycloalkyl, C1-C6alkoxy, amino, sulfonyl, (C1-C3 alkyl)sulfonyl, NO2, OH, SH, halo, haloalkyl, carboxyl, amido; J is a single 3 to 10-membered saturated or partially unsaturated alkylene chain that extends from the R7/R7′ cycloalkyl to G and forms a macrocycle, which chain is optionally interrupted by one to three heteroatoms independently selected from: —O—, —S— or —NR12—, and wherein 0 to 3 carbon atoms in the chain are optionally substituted with R14; wherein; R12 is H, C1-C6 alkyl, C3-C6cycloalkyl, or COR13; R13 is C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl; R14 is independently selected from H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, hydroxyl, halo, amino, oxo, thio, or C1-C6 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; R16 is H; or R16 is C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, any of which can be substituted with halo, oxo, nitrile, azido, nitro, C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, NH2CO—, Y—NRaRb, Y—O—Rb, Y—C(O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSOpRb, Y—S(═O)pRb, Y—S(═O)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: 3. A compound according to claim 1, with the partial structure 4. A compound according to claim 3, wherein Rq is C1-C3 alkyl. 5. A compound according to claim 1, wherein R16H, C1-C6alkyl or C3-C6cycloalkyl. 6. A compound according to claim 1, wherein W is —O—. 7. A compound according to claim 6 wherein R8 is optionally substituted C0-C3alkylcarbocyclyl or optionally substituted C0-C3alkylheterocyclyl. 8. A compound according to claim 7, wherein the C0-C3 alkyl moiety is methylene. 9. A compound of formula VI: wherein A is C(═O)NHSO2R2, or C(═O)OR1 wherein; R1 is H or C1-C6alkyl; R7 is C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl; wherein R2, is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, NH2C(═O)—, Y—NRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSOpRb, Y—S(═O)Rb, Y—S(═O)pNRaRb, Y—C(═O)ORb and Y—NRaC(═O)ORb; Y is independently a bond or C1-C3alkylene; Ra is independently H or C1-C3alkyl; Rb is independently H, C1-C6alkyl, C0-C3alkylcarbocyclyl or C0-C3alkylheterocyclyl; p is independently 1 or 2; M is CR7R7′; R7′ taken together with R7 forms a C3-C6cycloalkyl 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 C1-C6 alkyl; W is —O—, or —S—; J is a single 3 to 10-membered saturated or partially unsaturated alkylene chain that extends from the R7/R7′ cycloalkyl to G and forms a macrocycle, which chain is optionally interrupted by one to three heteroatoms independently selected from: —O—, —S— or NR12—, and wherein 0 to 3 carbon atoms in the chain are optionally substituted with R14; wherein; R12 is H, C1-C6 alkyl, C3-C6cycloalkyl, or COR13; R13 is C1-C6 alkyl, C0-C3alkylcycloalkyl, or C0-C3alkylheterocyclyl; R14 independently selected from H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, hydroxy, halo, amino, oxo, thio, or C1-C6 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; R16 is H; or R16 is C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, any of which can be substituted with halo, oxo, nitrile, azido, nitro, C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, NH2CO—, Y—NRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSOpRb, Y—S(═O)Rb, Y—S(═O)pNRaRb, Y—C(O)ORb, Y—NRaC(O)ORb; wherein R8 is C0-C3alkylaryl, or C0-C3alkylheteroaryl, either of which is optionally mono, di, or tri substituted with R9, wherein; R9 is C1-C6 alkyl, C1-C6alkoxy, NO2, OH, halo, trifluoromethyl, amino or amido optionally mono- or di-substituted with C1-C6alkyl, carboxy, C0-C3alkylaryl, or C0-C3alkylheteroaryl, the aryl or heteroaryl being optionally substituted with R10; wherein R10 is C1-C6alkyl, C3-C7cycloalkyl, C1-C6alkoxy, amino optionally mono- or di-substituted with C1-C6alkyl, C1-C3 alkyl amide, sulfonylC1-C3alkyl, NO2, OH, halo, trifluoromethyl, carboxyl, or heteroaryl or a pharmaceutically acceptable salt thereof. 10. A compound according to claim 9 wherein R9 is C1-C6 alkyl, C1-C6alkoxy, amino, di-(C1-C3 alkyl)amino, C1-C3alkylamide, aryl or heteroaryl, the aryl or heteroaryl being optionally substituted with R10; wherein R10 is C1-C6alkyl, C3-C7cycloalkyl, C1-C6alkoxy, amino, mono- or di-C1-C3 alkylamino, amido, C1-C3 alkylamide, halo, trifluoromethyl, or heteroaryl. 11. A compound according to claim 10, wherein, R10 is C1-C6alkyl, C1-C6alkoxy, amino optionally mono- or di-substituted with C1-C3 alkyl, amido, C1-C3-alkylamide, halo, or heteroaryl. 12. A compound according to claim 10 wherein R10 is methyl, ethyl, isopropyl, tert-butyl, methoxy, chloro, amino optionally mono- or di substituted with C1-C3 alkyl, amido, C1-C3alkylamide, or C1-C3alkyl thiazolyl. 13. A compound according to claim 8, wherein R8 is 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 1-naphthyl, 2-napthyl, or quinolinyl any of which is unsubstituted, mono, or disubstituted with R9 as defined. 14. A compound according to claim 13 wherein R8 is 1-naphthylmethyl, or quinolinyl any of which is unsubstituted, mono, or disubstituted with R9 as defined. 15. A compound according to claim 14 wherein R8 is: wherein R9a is C1-C6 alkyl; C1-C6alkoxy; thioC1-C3alkyl; amino optionally substituted with C1-C6alkyl; C0-C3alkylaryl; or C0-C3alkylheteroaryl, C0-C3alkylheterocyclyl, said aryl, heteroaryl or heterocycle being optionally substituted with R10 wherein R10 is C1-C6alkyl, C0-C3alkyl, C3-C7cycloalkyl, C1-C6alkoxy, amino optionally mono- or di-substituted with C1-C6alkyl, amido, C1-C3alkyl amide; and R9b is C1-C6 alkyl, C1-C6-alkoxy, amino, di(C1-C3alkyl)amino, (C1-C3alkyl) amide, NO2, OH, halo, trifluoromethyl, carboxyl. 16. A compound according to claim 15, wherein R9a is aryl or heteroaryl, either of which is optionally substituted with R10 as defined. 17. A compound according to 16, wherein R9a is selected from the group consisting of: wherein R10 is H, C1-C6alkyl, or C0-C3alkylcycloalkyl, amino optionally mono- or di-substituted with C1-C6alkyl, amido, (C1-C3alkyl)amide. 18. A compound according to claim 16, wherein R9a is optionally substituted phenyl, preferably phenyl substituted with C1-C6alkyl; C1-C6alkoxy; or halo. 19. A compound according to claim 15, wherein R8 is: wherein R10a is H, C1-C6alkyl, C0-C3alkylcarbocyclyl, amino optionally mono- or di-substituted with C1-C6alkyl, amido, (C1-C3 alkyl)amide, heteroaryl or heterocyclyl; and R9b is C1-C6 alkyl, C1-C6-alkoxy, amino, di(C1-C3 alkyl)amino, (C1-C3 alkyl)amide, NO2, OH, halo, trifluoromethyl, or carboxyl. 20. A compound according to any claim 15, wherein R9b is C1-C6-alkoxy, preferably methoxy. 21. A compound according to claim 1, wherein R2 is optionally substituted C1-C6 alkyl. 22. A compound according to claim 21, wherein R2 is methyl. 23. A compound according to claim 1, wherein R2 is optionally substituted C3-C7cycloalkyl. 24. A compound according to claim 1, wherein R2 is optionally substituted C0-C6alkylaryl. 25. A compound according to claim 1, wherein A is C(═O)OR1 wherein R1 is H. 26. A compound according to claim 1 wherein A is C(═O)OR1, wherein R1 is H or C1-C6 alkyl. 27. A compound according to claim 1, wherein R7 and R7′ 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 —NR12—, wherein R12 is H, C1-C6 alkyl, or —C(═O)C1-C6 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 R16 is H or methyl. 36. A compound according to claim 23, wherein R2 is cyclopropyl. 37. A compound according to claim 9, with the partial structure: 38. A compound according to claim 9, with the partial structure 39. A compound according to claim 38, wherein Rq is C1-C3 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 C0-C3 alkyl moiety of R9 is a bond. 43. A compound according to claim 9, wherein R16 is H or methyl. 44. A compound according to claim 9, wherein R2 is optionally substituted C3-C7cycloalkyl. 45. A compound according to claim 44, wherein R2 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 —NR12—, wherein R12 is H, or C1-C6 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)NHSO2R2; R2 is C0-C3alkylcarbocyclyl; 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 R7/R4′ cycloalkyl to G and forms a macrocycle; G is —NRy-; Ry is J; R16 is C1-C6alkyl; R8 is heteroaryl, which is optionally mono, di, or tri substituted with R9, wherein; R9 is C1-C6 alkyl, C1-C6alkoxy, or heteroaryl, the heteroaryl being optionally substituted with R10; wherein R10 is C1-C6alkyl. 51. A compound according to claim 9 wherein R2 is cyclopropyl; Rz is H; Rq is H; W is —O—; and J is a single mono-unsaturated alkylene chain that extends from the R7/R7′ 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[14.3.0.0.4.6]nonadec-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[14.3.0.0.4.6]nonadec-7-ene-4-carboxylic 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-carboxylic acid ethyl ester; 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-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-yloxy)-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4,6*]octadec-7-en-13-yl]-carbamic acid tert.butyl ester; Cyclopropanesulphonic acid[13-amino-17-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13-diaza-tricyclo[13.3 trifluoroacetic acid salt; Cyclopropanesulphonic acid {17-[2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-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-diaza-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-methyl-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-methyl-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-methyl-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 R2 is optionally substituted phenyl. 57. A compound according to claim 1, wherein A is C(═O)OR1, wherein R1 is methyl, ethyl, or tert-butyl.