Details for Patent: 9,856,265

Title:	Macrocyclic 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 (Gothenburg, SE), Samuelsson; Bengt Bertil (Skarholmen, SE), Rosenquist; Asa Annica Kristina (Huddinge, SE), Ivanov; Vladimir (Moscow, RU), Pelcman; Mikael (Alvsjo, SE), Belfrage; Anna Karin Gertrud Linnea (Uppsala, SE), Johansson; Per-Ola Mikael (Huddinge, SE), Vendeville; Sandrine Marie Helene (Etterbeek, BE)
Assignee:	Janssen Sciences Ireland UC (Little Island, Co. Cork, IE) Medivir AB (Huddinge, SE)
Filing Date:	Mar 09, 2017
Application Number:	15/454,911
Claims:	1. A compound of formula (I-d) ##STR00195## wherein n is 3, 4, 5, or 6; R.sup.1 is --NHSO.sub.2R.sup.8; R.sup.2 is hydrogen; R.sup.3 is hydrogen or C.sub.1-6alkyl; R.sup.4 is Het, wherein Het 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, or sulfur, and wherein said Het as a whole is optionally substituted with one, two, or three substituents each independently selected from halo, hydroxy, cyano, carboxyl, C.sub.1-6alkyl, C.sub.1-6alkoxy, or C.sub.1-6alkoxyC.sub.1-6alkyl; R.sup.5 is C.sub.1-6alkyl; R.sup.6 is C.sub.1-6alkoxy; and R.sup.8 is C.sub.3-7cycloalkyl optionally substituted with C.sub.1-6alkyl or a pharmaceutically acceptable salt thereof or a stereochemically isomeric form thereof or a pharmaceutically acceptable salt of the stereochemically isomeric form. 2. The compound of claim 1, wherein R.sup.4 is ##STR00196## wherein R.sup.4a is hydrogen, halo, C.sub.1-6alkyl, amino, or mono- or di-C.sub.1-6alkylamino; or a pharmaceutically acceptable salt thereof or a stereochemically isomeric form thereof or a pharmaceutically acceptable salt of the stereochemically isomeric form. 3. The compound of claim 1, wherein n is 4 or 5; or a pharmaceutically acceptable salt thereof or a stereochemically isomeric form thereof or a pharmaceutically acceptable salt of the stereochemically isomeric form. 4. The compound of claim 1, that is a pharmaceutically acceptable salt of the compound of formula I-d. 5. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof or a stereochemically isomeric form thereof or a pharmaceutically acceptable salt of the stereochemically isomeric form, and a pharmaceutically acceptable carrier. 6. The pharmaceutical composition of claim 5, comprising an amount of the compound of claim 1 that is sufficient to treat a hepatitis C virus (HCV) infection in a human. 7. A combination comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof or a stereochemically isomeric form thereof or a pharmaceutically acceptable salt of the stereochemically isomeric form; and another anti-HCV agent. 8. The combination of claim 7, wherein the other anti-HCV agent 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 a combination thereof. 9. The combination of claim 7, wherein the other anti-HCV agent is an HCV polymerase inhibitor, an HCV protease inhibitor, an antiviral agent, or a combination thereof. 10. The combination of claim 7, wherein the other anti-HCV agent is an HCV polymerase inhibitor. 11. The combination of claim 7, wherein the other anti-HCV agent is an HCV protease inhibitor. 12. The combination of claim 7, wherein the other anti-HCV agent is an antiviral agent. 13. The combination of claim 7, wherein the other anti-HCV agent is ribavirin. 14. The combination of claim 7, wherein the other anti-HCV agent is pegylated interferon-.alpha.. 15. The combination of claim 7, wherein the other anti-HCV agent is ribavirin and pegylated interferon-.alpha.. 16. A method of treating a hepatitis C virus infection in a patient comprising administering to the patient a compound of claim 1, or a pharmaceutically acceptable salt thereof or a stereochemically isomeric form thereof or a pharmaceutically acceptable salt of the stereochemically isomeric form, in an amount effective to treat the hepatitis C virus infection in the patient. 17. The method of claim 16, further comprising administration of another anti-HCV agent. 18. The method of claim 17, wherein the other anti-HCV agent 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 a combination thereof. 19. The method of claim 17, wherein the other anti-HCV agent is an HCV polymerase inhibitor, an HCV protease inhibitor, an antiviral agent, or a combination thereof. 20. The method of claim 17, wherein the other anti-HCV agent is pegylated interferon-.alpha. and/or ribavirin.