Claims for Patent: 8,754,106

Summary for Patent: 8,754,106

Title:	Macrocyclic inhibitors of hepatitis C virus
Abstract:	Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; R1 is —OR7, —NH—SO2R8; R2 is hydrogen, and where X is C or CH, R2 may also be C1-6alkyl; R3 is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, C3-7cycloalkyl; R4 is aryl or Het; n is 3, 4, 5, or 6; R5 is halo, C1-6alkyl, hydroxy, C1-6alkoxy, phenyl, or Het; R6 is C1-6alkoxy, or dimethylamino; R7 is hydrogen; aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; R8 is aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; aryl is phenyl optionally substituted with one, two or three substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.
Inventor(s):	Kenneth Alan Simmen, Herman Augustinus De Kock, Pierre Jean-Marie Bernard Raboisson, Lili Hu, Abdellah Tahri, Dominique Louis Nestor Ghislain Surleraux, Karl Magnus Nilsson, Bengt Bertil Samuelsson, Asa Annica Kristina Rosenquist, Vladimir Ivanov, Mikael Pelcman, Anna Karin Gertrud Linea Belfrage, Per-Ola Mikael Johansson, Sandrine Marie Helene Vendeville
Assignee:	Janssen Sciences Ireland ULC, Medivir AB
Application Number:	US13/832,166
Patent Claims:	1. A combination comprising: (a) a compound having the formula an N-oxide, salt, or stereoisomer thereof, wherein each dashed line (represented by - - - - -) represents an optional double bond; X is N, CH and where X bears a double bond it is C; R1 is —OR7, —NH—SO2R8; R2 is hydrogen, and where X is C or CH, R2 may also be C1-6alkyl; R3 is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, C3-7cycloalkyl; R4 is aryl or Het; n is 3, 4, 5, or 6; R5 represents halo, C1-6alkyl, hydroxy, C1-6alkoxy, polyhaloC1-6alkyl, phenyl, or Het; R6 represents C1-6alkoxy, or dimethylamino; R7 is hydrogen; aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; R8 is aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; aryl as a group or part of a group is phenyl optionally substituted with one, two or three substituents selected from halo, hydroxy, nitro, cyano, carboxyl, C1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkylcarbonyl, amino, mono- or di-C1-6alkylamino, azido, mercapto, polyhaloC1-6alkyl, polyhaloC1-6alkoxy, C3-7cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl, 4-C1-6alkylcarbonylpiperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or with two C1-6alkyl radicals; Het as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally condensed with a benzene ring; and wherein said Het as a whole is optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, carboxyl, C1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkylcarbonyl, amino, mono- or di-C1-6alkylamino, azido, mercapto, polyhaloC1-6alkyl, polyhaloC1-6alkoxy, C3-7cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl, 4-C1-6alkylcarbonylpiperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or with two C1-6alkyl radicals; and (b) another anti-HCV compound. 2. The combination according to claim 1, wherein the compound of formula (I) has the formula (I-c), (I-d), or (I-e): 3. The combination according to claim 1 wherein the compound of formula (I) has the formula (I-b): 4. The combination according to claim 3 wherein R2 is hydrogen; and a double bond is present between carbon atoms 7 and 8. 5. The combination according to claim 1, wherein R4 is selected from the group consisting of phenyl, pyridin-4-yl, wherein R4a is, each independently, hydrogen, halo, C1-6alkyl, amino, or mono- or di-C1-6alkylamino. 6. The combination according to claim 1, wherein R4 is a radical wherein, where possible, a nitrogen may bear an R4a substituent or a link to the remainder of the molecule; each R4a in any of the R4 substituents may be selected from those mentioned as possible substituents on Het, as specified in claim 1. 7. The combination according to claim 1, wherein R4 is: wherein each R4a is hydrogen, halo, C1-6alkyl, amino, or mono- or di-C1-6alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or 4-C1-6alkylpiperazinyl; and wherein the morpholinyl and piperidinyl groups may optionally be substituted with one or two C1-6alkyl radicals. 8. The combination according to claim 7, wherein in radicals (q-1), (q-2), (q-3), or (q-4) each R4a is independently, hydrogen, halo, C1-6alkyl, amino, or mono- or di-C1-6alkylamino. 9. The combination according to claim 1, wherein R5 is methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or bromo. 10. The combination according to claim 1, wherein (a) R1 is —OR7, wherein R7 is C1-6alkyl or hydrogen; (b) R1 is —NHS(═O)2R8, wherein R8 is methyl, cyclopropyl, or phenyl; or R1 is —NHS(═O)2R8, wherein R8 is cyclopropyl substituted with methyl. 11. The combination according to claim 10, wherein R1 is —NHS(═O)2R8, wherein R8 is methyl, cyclopropyl, or phenyl. 12. The combination according to claim 1, wherein n is 4 or 5. 13. The combination according to claim 12, wherein n is 4. 14. The combination according to claim 1, wherein R3 is hydrogen or C1-6alkyl. 15. The combination according to claim 14 wherein R3 is hydrogen or methyl. 16. The combination according to claim 1, wherein R6 is methoxy. 17. The combination according to claim 1 wherein the compound of formula (I) is: 18. The combination according to claim 1 wherein the compound of formula (I) is: 19. The combination according to claim 1 wherein the compound of formula (I) is: 20. The combination according to claim 1 other than an N-oxide, or salt. 21. The combination according to claim 1 other than an N-oxide. 22. The combination as claimed in claim 1, wherein the other anti-HCV compound is an HCV polymerase inhibitor, an HCV protease inhibitor, an inhibitor of another target in the HCV life cycle, an immunomodulatory agent, an antiviral agent, or combinations thereof. 23. The combination as claimed in claim 22, wherein the other anti-HCV compound is an HCV polymerase inhibitor. 24. The combination as claimed in claim 22, for simultaneous, separate, or sequential use in the treatment of HCV infections. 25. The combination as claimed in claim 23, for simultaneous, separate, or sequential use in the treatment of HCV infections. 26. A method of inhibiting HCV replication comprising administering to a patient in need thereof, a compound of formula (I) an N-oxide, salt, or stereoisomer thereof, wherein each dashed line (represented by - - - - -) represents an optional double bond; X is N, CH and where X bears a double bond it is C; R1 is —OR7, —NH—SO2R8; R2 is hydrogen, and where X is C or CH, R2 may also be C1-6alkyl; R3 is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, C3-7cycloalkyl; R4 is aryl or Het; n is 3, 4, 5, or 6; R5 represents halo, C1-6alkyl, hydroxy, C1-6alkoxy, polyhaloC1-6alkyl, phenyl, or Het; R6 represents C1-6alkoxy, or dimethylamino; R7 is hydrogen; aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; R8 is aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; aryl as a group or part of a group is phenyl optionally substituted with one, two or three substituents selected from halo, hydroxy, nitro, cyano, carboxyl, C1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkylcarbonyl, amino, mono- or di-C1-6alkylamino, azido, mercapto, polyhaloC1-6alkyl, polyhaloC1-6alkoxy, C3-7cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-Ci-6alkylpiperazinyl, 4-C1-6alkylcarbonylpiperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or with two C1-6alkyl radicals; Het as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally condensed with a benzene ring; and wherein said Het as a whole is optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, carboxyl, C1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkylcarbonyl, amino, mono- or di-C1-6alkylamino, azido, mercapto, polyhaloC1-6alkyl, polyhaloC1-6alkoxy, C3-7cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl, 4-C1-6alkylcarbonylpiperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or with two C1-6alkyl radicals; in combination with another compound. 27. The method as claimed in claim 26, wherein the other compound is another anti-HCV compound. 28. The method as claimed in claim 27, wherein the other anti-HCV compound is an HCV polymerase inhibitor, and HCV protese inhibitor, an inhibitor of another target in the HCV life cycle, an immunomodulatory agent, an antiviral agent, or combinations thereof. 29. The method as claimed in claim 27, wherein the other anti-HCV compound is an HCV polymerase inhibitor. 30. The method as claimed in claim 28, wherein the combination therapy is for simultaneous, separate, or sequential use in the treatment of HCV infections. 31. The method as claimed in claim 28, wherein the combination therapy is for simultaneous, separate, or sequential use in the treatment of HCV infections. 32. A pharmaceutical composition comprising a carrier, and as active ingredient an anti-virally effective amount of a combination comprising: (a) a compound having the formula an N-oxide, salt, or stereoisomer thereof, wherein each dashed line (represented by - - - - -) represents an optional double bond; X is N, CH and where X bears a double bond it is C; R1 is —OR7, —NH—SO2R8; R2 is hydrogen, and where X is C or CH, R2 may also be C1-6alkyl; R3 is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, C3-7cycloalkyl; R4 is aryl or Het; n is 3, 4, 5, or 6; R5 represents halo, C1-6alkyl, hydroxy, C1-6alkoxy, polyhaloC1-6alkyl, phenyl, or Het; R6 represents C1-6alkoxy, or dimethylamino; R7 is hydrogen; aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; R8 is aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; aryl as a group or part of a group is phenyl optionally substituted with one, two or three substituents selected from halo, hydroxy, nitro, cyano, carboxyl, C1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkylcarbonyl, amino, mono- or di-C1-6alkylamino, azido, mercapto, polyhaloC1-6alkyl, polyhaloC1-6alkoxy, C3-7cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl, 4-C1-6alkylcarbonylpiperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or with two C1-6alkyl radicals; Het as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally condensed with a benzene ring; and wherein said Het as a whole is optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, carboxyl, C1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkylcarbonyl, amino, mono- or di-C1-6alkylamino, azido, mercapto, polyhaloC1-6alkyl, polyhaloC1-6alkoxy, C3-7cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl, 4-C1-6alkylcarbonylpiperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or with two C1-6alkyl radicals; and (b) another anti-HCV compound. 33. The pharmaceutical composition of claim 32 wherein the anti-HCV compund is an HCV polymerase inhibitor, an HCV protease inhibitor, an inhibitor of another target in the HCV life cycle, an immunomodulatory agent, an antiviral agent, or combinations thereof. 34. The pharmaceutical composition of claim 32 wherein the anti-HCV compound is an HCV polymerase inhibitor.