Claims for Patent: 8,349,869

Summary for Patent: 8,349,869

Title:	Macrocylic 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, Åsa 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:	US13/412,997
Patent Claims:	1. A compound of formula (I): an N-oxide, pharmaceutically acceptable 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 or —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, or C3-7cycloalkyl; R4 is aryl or Het; n is 3, 4, 5, or 6; R5 is halo, C1-6alkyl, hydroxy, polyhaloC1-6alkyl, 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 Het; R8 is aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or Het; aryl as a group or part of a group is phenyl optionally substituted with one, two or three substituents that is 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, or morpholinyl; wherein the morpholinyl and piperidinyl groups are 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 the group consisting of nitrogen, oxygen and sulfur, said heterocyclic ring being optionally connected 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 are optionally substituted with one or with two C1-6alkyl radicals. 2. The compound according to claim 1, wherein the compound has the formula (I-c), (I-d), or (I-e): 3. The compound according to claim 1, wherein R4 is phenyl, pyridin-4-yl, wherein R4a is hydrogen, halo, C1-6alkyl, amino, or mono- or di-C1-6alkylamino. 4. The compound according to claim 1, wherein R5 is methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or bromo; and R6 is methoxy. 5. The compound according to claim 1, wherein R1 is —OR7, wherein R7 is C1-6alkyl or hydrogen. 6. The compound according to claim 1, wherein R1 is —NHS(═O)2R8, wherein R8 is methyl, cyclopropyl, or phenyl. 7. The compound according to claim 1, wherein R1 is —NHS(═O)2R8, wherein R8 is cyclopropyl substituted with methyl. 8. The compound according to claim 1, wherein n is 4 or 5. 9. The compound according to claim 1, wherein n is 4. 10. The compound according to claim 1, wherein R3 is hydrogen or C1-6alkyl. 11. The compound according to claim 10, wherein R3, is hydrogen or methyl. 12. The compound according to claim 1, wherein R4 is wherein, when possible, a nitrogen optionally bears an R4a substituent or a link to the remainder of the molecule; and each R4a in any of the R4 substituents is Het. 13. The compound 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 are optionally substituted with one or two C1-6alkyl radicals. 14. The compound according to claim 13, 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. 15. The compound according to claim 1, wherein R6 is methoxy. 16. The compound according to claim 1 wherein the compound of formula (I) is: 17. The compound according to claim 16, wherein R2 is hydrogen and a double bond is present between carbon atoms 7 and 8. 18. The compound according to claim 1 wherein the compound of formula (I) is: 19. The compound according to claim 1 wherein the compound of formula (I) is: 20. The compound according to claim 1 wherein the compound of formula (I) is: 21. The compound according to claim 1 other than an N-oxide, or salt. 22. The compound according to claim 1 other than an N-oxide. 23. A combination comprising (a) a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof; and (b) ritonavir, or a pharmaceutically acceptable salt thereof. 24. A combination comprising (a) a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof; and (b) interferon-α, pegylated interferon-α, and/or ribavirin. 25. A pharmaceutical composition comprising a carrier, and as active ingredient, an anti-virally effective amount of a compound as claimed in claim 1. 26. A pharmaceutical composition comprising a carrier, and as active ingredient, an anti-virally effective amount of a combination according to claim 23 or claim 24. 27. A method of inhibiting HCV replication comprising administering to a patient in need thereof, a compound according to claim 1. 28. A method of inhibiting HCV replication comprising administering to a patient in need thereof, a combination according to claim 23 or 24. 29. A process for preparing a compound according to claim 1 comprising: (a) preparing a compound of formula (I) wherein the bond between C7 and C9 is a double bond, which is a compound of formula (I-i), by forming a double bond between C7 and C8 with concomitant cyclization to the macrocycle as outlined in the following reaction scheme: wherein in the above and following reaction schemes R9 is: (b) converting the compound of formula (I-i) to a compound, of formula (I-j) wherein the link between C7 and C8 in the macrocycle is a single bond: by reducing the C7-C8 double bond in the compound of formula (I-j); (c) preparing a compound of formula (I) wherein R1 is —NHSO2R8, said compounds represented by formula (I-k-1), by forming an amide bond between an intermediate (2a) and an sulfonylamine (2b), or preparing a compound of formula (I) wherein R1 represents —OR7, said compounds represented by formula (I-k-2), by forming an ester bond between an intermediate (2a) and an alcohol (2c) as outlined in the following scheme wherein G represents a group: (d) preparing a compound of formula (I) wherein R3 is hydrogen, said compound represented by (I-1), from a corresponding nitrogen-protected intermediate (3a), wherein PG represents a nitrogen protecting group: (e) reacting an intermediate (4a) with intermediate (4b) as outlined in the following reaction scheme: wherein Y in (4b) represents hydroxy or a leaving group; and where Y represents hydroxy the reaction of (4a) with (4b) is a Mitsunobu reaction; and where Y represents a leaving group the reaction of (4a) with (4b) is a substitution reaction; (f) converting compounds of formula (I) into each other by a functional group transformation reaction; or (g) preparing a salt form by reacting the free form of a compound of formula (I) with an acid or a base. 30. The process of claim 29, wherein the formation of the double bond between C7 and C8 with concomitant cyclization to the macrocycle of step (a) is via an olefin metathesis reaction.