Claims for Patent: RE46762

Summary for Patent: RE46762

Title:	1′-substituted carba-nucleoside analogs for antiviral treatment
Abstract:	Provided are pyrrolo[1,2-f][1,2,4]triazinyl, imidazo[1,5-f][1,2,4]triazinyl, imidazo[1,2-f][1,2,4]triazinyl, and [1,2,4]triazolo[4,3-f][1,2,4]triazinyl nucleosides, nucleoside phosphates and prodrugs thereof, wherein the 1′ position of the nucleoside sugar is substituted. The compounds, compositions, and methods provided are useful for the treatment of Flaviviridae virus infections, particularly hepatitis C infections.
Inventor(s):	Thomas Butler, Aesop Cho, Choung U. Kim, Jay P. Parrish, Oliver L. Saunders, Lijun Zhang
Assignee:	Gilead Sciences Inc
Application Number:	US15/288,271
Patent Claims:	1. A compound of Formula II: or a pharmaceutically acceptable salt, thereof; wherein: R1, R3, and R5 are H; R2 and R4 are, independently, ORa; R6 is ORa, N3, CN, S(O)nRa, —C(═O)R11, —C(═O)OR11, —C(═O)NR11R12, —C(═O)SR11, —S(O)R11, —S(O)2R11, —S(O)(OR11), —S(O)2(OR11), —SO2NR11R12, halogen, substituted methyl, ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl; each n is independently 0, 1, or 2; each Ra is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C1-C8)alkyl, (C4-C8)carbocyclylalkyl, —C(═O)R11, —C(═O)OR11, —C(═O)NR11R12, C(═O)SR11, S(O)R11, —S(O)2R11, —S(O)(OR11), —S(O)2(OR11), or —SO2NR11R12; R7 is H, —C(═O)R11, —C(═O)OR11, —C(═O)NR11R12, —C(═O)SR11, —S(O)R11, —S(O)2R11, —S(O)(OR11), —S(O)2(OR11), —SO2NR11R12, or W1 and W2, when taken together, are —Y3(C(Ry)2)3Y3—; or W1 and W2 are each, independently, a group of the Formula Ia: Y and each Y1 are independently O, S, NR, +N(O)(R) +N(O−)(R), N(OR), +N(O)(OR) +N(O−)(OR), or N—NR2; each Y2 is independently a bond, O, CR2, NR, +N(O)(R) +N(O−)(R), N(OR), +N(O)(OR) +N(O−)(OR), N—NR2, S, S—S, S(O), or S(O)2; each Y3 is independently O, S, or NR; M2 is 0, 1 or 2; each Rx is independently Ry or the formula: wherein: each M1a, M1c, and M1d is independently 0 or 1; M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; each Ry is independently H, F, Cl, Br, I, OH, R, —C(═Y1)R, —C(═Y1)OR, —C(═Y1)N(R)2, —N(R)2, —+N(R)3 —+N(R)3, —SR, —S(O)R, —S(O)2R, —S(O)(OR), —S(O)2(OR), —OC(═Y1)R, —OC(═Y1)OR, —OC(═Y1)(N(R)2), —SC(═Y1)R, —SC(═Y1)OR, —SC(═Y1)(N(R)2), —N(R)C(═Y1)R, —N(R)C(═Y1)OR, —N(R)C(═Y1)N(R)2, —SO2NR2, —CN, —N3, —NO2, —OR, or W3; or when taken together, two Ry on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms; each R is independently H, (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8)alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heterocyclyl, C2-C20 substituted heterocyclyl, arylalkyl or substituted arylalkyl; W3 is W4 or W5; W4 is R, —C(Y1)Ry, —C(Y1)W5, —SO2Ry, or —SO2W5; and W5 is a carbocycle or a heterocycle wherein W5 is independently substituted with 0 to 3 Ry groups; X2 is C—R10 and X1 is C—R10 or N; R8 is halogen, NR11R12, N(R11)OR11, NR11NR11R12, N3, NO, NO2, CHO, CN, —CH(═NR11), —CH═NHNR11, —CH═N(OR11), —CH(OR11)2, —C(═O)NR11R12, —C(═S)NR11R12, —C(═O)OR11, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C1-C8)alkyl, —S(O)nC1-C8)alkyl —S(O)n(C1-C8)alkyl, aryl(C1-C8)alkyl, OR11 or SR11; R9 and each R10 are independently H, halogen, NR11R12, N(R11)OR11, NR11NR11R12, N3, NO, NO2, CHO, CN, —CH(═NR11), —CH═NHNR11, —CH═N(OR11), —CH(OR11)2, —C(═O)NR11R12, —C(═S)NR11R12, —C(═O)OR11, R11, OR11 or SR11; each R11 and each R12 are independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C1-C8)alkyl, —S(O)n(C1-C8)alkyl or aryl(C1-C8)alkyl; or R11 and R12 taken together with a nitrogen to which they are both attached to form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S— or —NRa—; wherein substituted methyl, substituted ethenyl and substituted ethynyl of R6 and each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or aryl(C1-C8)alkyl of each of R11 and R12 are independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(Ra)2 or ORa; and wherein one or more of the non-terminal carbon atoms of each said (C1-C8)alkyl is optionally replaced with —O—, —S— or —NRa—. 2. The compound according to claim 1, wherein R6 is ORa, N3, halogen, CN, substituted methyl, ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl. 3. The compound according to claim 1, wherein R2 and R4 are OH. 4. The compound according to claim 2, wherein R2 and R4 are OH. 5. The compound according to claim 1, wherein R6 is CN. 6. The compound according to claim 4, wherein R6 is CN. 7. The compound according to claim 4, wherein R9 is NR11R12. 8. The compound according to claim 7, wherein X2 is C—H. 9. The compound according to claim 8, wherein X1 is C—H. 10. The compound according to claim 9, wherein R7 is H. 11. The compound according to claim 9, wherein 12. A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof. 13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. 14. The pharmaceutical composition of claim 13 further comprising at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin analogs, NS3 protease inhibitors, NS5a inhibitors, NS5b polymerase inhibitors, alphaglucosidase alpha-glucosidase 1 inhibitors, cyclophilin inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV. 15. A method of inhibiting HCV polymerase comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1. 16. A method of treating a viral infection caused by a virus selected from the group consisting of dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus and Hepatitis C virus comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of claim 1. 17. The method of claim 16, wherein the viral infection is caused by Hepatitis C virus. 18. The method of claim 17 further comprising administering at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin analogs, NS3 protease inhibitors, NS5b polymerase inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, cyclophilin inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV. 19. The method of claim 16, wherein the viral infection is caused by Zika virus. 20. A compound of or a pharmaceutically acceptable salt, thereof; wherein: R1, R3, and R5 are H; R2 and R4 are OH; R6 is CN; each Ra is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C1-C8)alkyl, (C4-C8)carbocyclylalkyl, —C(═O)R11, —C(═O)OR11, —C(═O)NR11R12, C(═O)SR11, S(O)R11, —S(O)2R11, —S(O)(OR11), —S(O)2(OR11), or —SO2NR11R12; R7 is W1 and W2, when taken together, are —Y3(C(Ry)2)3Y3—; or W1 and W2 are each, independently, a group of the Formula Ia: Y and each Y1 are O, S, NR, +N(O−)(R), N(OR), +N(O−)(OR), or N—NR2; each Y2 is independently a bond, O, CR2, NR, +N(O−)(R), N(OR), +N(O−)(OR), N—NR2, S, S—S, S(O), or S(O)2; each Y3 is independently O, S, or NR; M2 is 0, 1 or 2; each Rx is independently Ry or the formula: wherein: each M1a, M1c, and M1d is independently 0 or 1; M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; each Ry is independently H, F, Cl, Br, I, OH, R, —C(═Y1)R, —C(═Y1)OR, —C(═Y1)N(R)2, —N(R)2, —+N(R)3, —SR, —S(O)R, —S(O)2R, —S(O)(OR), —S(O)2(OR), —OC(═Y1)R, —OC(═Y1)OR, —OC(═Y1)(N(R)2), —SC(═Y1)R, —SC(═Y1)OR, —SC(═Y1)(N(R)2), —N(R)C(═Y1)R, —N(R)C(═Y1)OR, —N(R)C(═Y1)N(R)2, —SO2NR2, —CN, —N3, —NO2, —OR, or W3; or when taken together, two Ry on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms; each R is independently H, (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8)alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heterocyclyl, C2-C20 substituted heterocyclyl, arylalkyl or substituted arylalkyl; W3 is W4 or W5; W4 is R, —C(Y1)Ry, —C(Y1)W5, —SO2Ry, or —SO2W5; and W5 is a carbocycle or a heterocycle wherein W5 is independently substituted with 0 to 3 Ry groups; X2 is C—H and X1 is C—H; R8 is halogen, NR11R12, N(R11)OR11, NR11NR11R12, N3, NO, NO2, CHO, CN, —CH(═NR11), —CH═NHNR11, —CH═N(OR11), —CH(OR11)2, —C(═O)NR11R12 , —C(═S)NR11R12, —C(═O)OR11, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C1-C8)alkyl, —S(O)n(C1-C8)alkyl, aryl(C1-C8)alkyl, OR11 or SR11; R9 is H, halogen, NR11R12, N(R11)OR11, NR11NR11R12, N3, NO, NO2, CHO, CN, —CH(═NR11), —CH═NHNR11, —CH═N(OR11), —CH(OR11)2, —C(═O)NR11R12, —C(═S)NR11R12, —C(═O)OR11, R11, OR11 or SR11; each R11 and each R12 are independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C1-C8)alkyl, —S(O)n(C1-C8)alkyl or aryl(C1-C8)alkyl; or R11 and R12 taken together with a nitrogen to which they are both attached to form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S— or —NRa—; wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or aryl(C1-C8)alkyl of each of R11 and R12 are independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(Ra)2 or ORa; and wherein one or more of the non-terminal carbon atoms of each said (C1-C8)alkyl is optionally replaced with —O—, —S— or —NRa—. 21. The compound of claim 20, wherein is selected from wherein Y2 is, independently, a bond, O, or CR2. 22. The compound of claim 20, wherein W1 and W2 are each, independently, a group of the Formula Ia. 23. A pharmaceutical composition comprising the compound of claim 20. 24. A method of treating a Flaviviridae viral infection in a human in need thereof by administering the compound of claim 20. 25. The method of treating a Flaviviridae viral infection of claim 24 wherein the Flaviviridae viral infection is caused by a Zika virus. 26. A method of treating a Flaviviridae viral infection by contacting a cell with the compound of claim 20. 27. The method of treating a Flaviviridae viral infection of claim 26 wherein the Flaviviridae viral infection is caused by a Zika virus. 28. A compound: 29. A pharmaceutical composition comprising the compound of claim 28. 30. A method of treating a Flaviviridae viral infection in a human in need thereof by administering the compound of claim 28. 31. The method of treating a Flaviviridae viral infection of claim 30 wherein the Flaviviridae viral infection is caused by a Zika virus. 32. A method of treating a Flaviviridae viral infection by contacting a cell with the compound of claim 28. 33. The method of treating a Flaviviridae viral infection of claim 32 wherein the Flaviviridae viral infection is caused by a Zika virus.