Details for Patent: 8,349,869

Title:	Macrocylic inhibitors of hepatitis C virus
Abstract:	Inhibitors of HCV replication of formula (I) ##STR00001## 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; R.sup.1 is --OR.sup.7, --NH--SO.sub.2R.sup.8; R.sup.2 is hydrogen, and where X is C or CH, R.sup.2 may also be C.sub.1-6alkyl; R.sup.3 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxyC.sub.1-6alkyl, C.sub.3-7cycloalkyl; R.sup.4 is aryl or Het; n is 3, 4, 5, or 6; R.sup.5 is halo, C.sub.1-6alkyl, hydroxy, C.sub.1-6alkoxy, phenyl, or Het; R.sup.6 is C.sub.1-6alkoxy, or dimethylamino; R.sup.7 is hydrogen; aryl; Het; C.sub.3-7cycloalkyl optionally substituted with C.sub.1-6alkyl; or C.sub.1-6alkyl optionally substituted with C.sub.3-7cycloalkyl, aryl or with Het; R.sup.8 is aryl; Het; C.sub.3-7cycloalkyl optionally substituted with C.sub.1-6alkyl; or C.sub.1-6alkyl optionally substituted with C.sub.3-7cycloalkyl, 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):	Simmen; Kenneth Alan (Tervuren, BE), De Kock; Herman Augustinus (Arendonk, BE), Raboisson; Pierre Jean-Marie Bernard (Sterrebeek, BE), Hu; Lili (Mechelen, BE), Tahri; Abdellah (Anderlecht, BE), Surleraux; Dominique Louis Nestor Ghislain (Braine-le-chateau, BE), Nilsson; Karl Magnus (Goteborg, SE), Samuelsson; Bengt Bertil (Skarholmen, SE), Rosenquist; .ANG.sa Annica Kristina (Huddinge, SE), Ivanov; Vladimir (Moscow, RU), Pelcman; Mikael (Alvsjo, SE), Belfrage; Anna Karin Gertrud Linea (Uppsala, SE), Johansson; Per-Ola Mikael (Huddinge, SE), Vendeville; Sandrine Marie Helene (Etterbeek, BE)
Assignee:	Tibotec Pharmaceuticals Ltd. (Eastgate, County Cork, IE) Medivir AB (Huddinge, SE)
Filing Date:	Mar 06, 2012
Application Number:	13/412,997
Claims:	1. A compound of formula (I): ##STR00194## 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; R.sup.1 is --OR.sup.7 or --NH--SO.sub.2R.sup.8; R.sup.2 is hydrogen, and where X is C or CH, R.sup.2 may also be C.sub.1-6alkyl; R.sup.3 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxyC.sub.1-6alkyl, or C.sub.3-7cycloalkyl; R.sup.4 is aryl or Het; n is 3, 4, 5, or 6; R.sup.5 is halo, C.sub.1-6alkyl, hydroxy, polyhaloC.sub.1-6alkyl, phenyl, or Het; R.sup.6 is C.sub.1-6alkoxy or dimethylamino; R.sup.7 is hydrogen; aryl; Het; C.sub.3-7cycloalkyl optionally substituted with C.sub.1-6alkyl; or C.sub.1-6alkyl optionally substituted with C.sub.3-7cycloalkyl, aryl or Het; R.sup.8 is aryl; Het; C.sub.3-7cycloalkyl optionally substituted with C.sub.1-6alkyl; or C.sub.1-6alkyl optionally substituted with C.sub.3-7cycloalkyl, 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, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6alkoxyC.sub.1-6alkyl, C.sub.1-6alkylcarbonyl, amino, mono- or di-C.sub.1-6alkylamino, azido, mercapto, polyhaloC.sub.1-6alkyl, polyhaloC.sub.1-6alkoxy, C.sub.3-7cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C.sub.1-6alkylpiperazinyl, 4-C.sub.1-6alkylcarbonylpiperazinyl, or morpholinyl; wherein the morpholinyl and piperidinyl groups are optionally substituted with one or with two C.sub.1-6alkyl 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, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6alkoxyC.sub.1-6alkyl, C.sub.1-6alkylcarbonyl, amino, mono- or di-C.sub.1-6alkylamino, azido, mercapto, polyhaloC.sub.1-6alkyl, polyhaloC.sub.1-6alkoxy, C.sub.3-7cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C.sub.1-6alkylpiperazinyl, 4-C.sub.1-6alkylcarbonylpiperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups are optionally substituted with one or with two C.sub.1-6alkyl radicals. 2. The compound according to claim 1, wherein the compound has the formula (I-c), (I-d), or (I-e): ##STR00195## 3. The compound according to claim 1, wherein R.sup.4 is phenyl, pyridin-4-yl, ##STR00196## wherein R.sup.4a is hydrogen, halo, C.sub.1-6alkyl, amino, or mono- or di-C.sub.1-6alkylamino. 4. The compound according to claim 1, wherein R.sup.5 is methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or bromo; and R.sup.6 is methoxy. 5. The compound according to claim 1, wherein R.sup.1 is --OR.sup.7, wherein R.sup.7 is C.sub.1-6alkyl or hydrogen. 6. The compound according to claim 1, wherein R.sup.1 is --NHS(.dbd.O).sub.2R.sup.8, wherein R.sup.8 is methyl, cyclopropyl, or phenyl. 7. The compound according to claim 1, wherein R.sup.1 is --NHS(.dbd.O).sub.2R.sup.8, wherein R.sup.8 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 R.sup.3 is hydrogen or C.sub.1-6alkyl. 11. The compound according to claim 10, wherein R.sup.3, is hydrogen or methyl. 12. The compound according to claim 1, wherein R.sup.4 is ##STR00197## wherein, when possible, a nitrogen optionally bears an R.sup.4a substituent or a link to the remainder of the molecule; and each R.sup.4a in any of the R.sup.4 substituents is Het. 13. The compound according to claim 1, wherein R.sup.4 is: ##STR00198## wherein each R.sup.4a is hydrogen, halo, C.sub.1-6alkyl, amino, or mono- or di-C.sub.1-6alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or 4-C.sub.1-6alkylpiperazinyl; and wherein the morpholinyl and piperidinyl groups are optionally substituted with one or two C.sub.1-6alkyl radicals. 14. The compound according to claim 13, wherein in radicals (q-1), (q-2), (q-3), or (q-4), each R.sup.4a is independently hydrogen, halo, C.sub.1-6alkyl, amino, or mono- or di-C.sub.1-6alkylamino. 15. The compound according to claim 1, wherein R.sup.6 is methoxy. 16. The compound according to claim 1 wherein the compound of formula (I) is: ##STR00199## 17. The compound according to claim 16, wherein R.sup.2 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: ##STR00200## 19. The compound according to claim 1 wherein the compound of formula (I) is: ##STR00201## 20. The compound according to claim 1 wherein the compound of formula (I) is: ##STR00202## 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-.alpha., pegylated interferon-.alpha., 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 C.sub.7 and C.sub.9 is a double bond, which is a compound of formula (I-i), by forming a double bond between C.sub.7 and C.sub.8 with concomitant cyclization to the macrocycle as outlined in the following reaction scheme: ##STR00203## wherein in the above and following reaction schemes R.sup.9 is: ##STR00204## (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: ##STR00205## by reducing the C7-C8 double bond in the compound of formula (I-j); (c) preparing a compound of formula (I) wherein R.sup.1 is --NHSO.sub.2R.sup.8, 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 R.sup.1 represents --OR.sup.7, 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: ##STR00206## (d) preparing a compound of formula (I) wherein R.sup.3 is hydrogen, said compound represented by (I-1), from a corresponding nitrogen-protected intermediate (3a), wherein PG represents a nitrogen protecting group: ##STR00207## (e) reacting an intermediate (4a) with intermediate (4b) as outlined in the following reaction scheme: ##STR00208## 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 C.sub.7 and C.sub.8 with concomitant cyclization to the macrocycle of step (a) is via an olefin metathesis reaction.