Claims for Patent: 8,008,264

Summary for Patent: 8,008,264

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 Parrish, Oliver L. Saunders, Lijun Zhang
Assignee:	Gilead Sciences Inc
Application Number:	US12/428,176
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,008,264
Patent Claims:	1. A compound of Formula I: or a pharmaceutically acceptable salt, thereof; wherein: each R1, R2, R3, R4, or R5 is independently H, ORa, N(Ra)2, N3, CN, NO2, S(O)nRa, halogen, (C1-C8)alkyl, (C4-C8)carbocyclylalkyl, (C1-C8)substituted alkyl, (C2-C8)alkenyl, (C2-C8)substituted alkenyl, (C2-C8)alkynyl, (C2-C8)substituted alkynyl, or aryl(C1-C8)alkyl; or any two R1, R2, R3, R4, or R5 on adjacent carbon atoms when taken together are —O(CO)O— or when taken together with the ring carbon atoms to which they are attached form a double bond; R6 is ORa, N(Ra)2, N3, CN, NO2, 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, (C1-C8)alkyl, (C4-C8)carbocyclylalkyl, (C1-C8)substituted alkyl, (C2-C8)alkenyl, (C2-C8)substituted alkenyl, (C2-C8)alkynyl, (C2-C8)substituted alkynyl, or aryl(C1-C8)alkyl or R6 and either R1 or R2 when taken together are —O(CO)O—; 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 Y is O, S, NR, +N(O)(R), N(OR), +N(O)(OR), or N—NR2; W1 and W2, when taken together, are —Y3(C(Ry)2)3Y3—; or one of W1 or W2 together with either R3 or R4 is —Y3— and the other of W1 or W2 is Formula Ia; or W1 and W2 are each, independently, a group of the Formula Ia: wherein: each Y1 is, independently, 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 a group of 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, —CN, —N3, —NO2, —OR, —C(═Y1)R, —C(Y1)W5, —C(═Y1)OR, —C(═Y1)N(R)2, —N(R)2, —+N(R)3, —SR, —S(O)R, —S(O)2R, —SO2W5, —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, W5, (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; wherein each alkyl, alkenyl, alkynyl, aryl, heterocyclyl, or arylalkyl is independently optionally substituted with one or more Z groups; or when taken together, two Ry on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms; each W5 is independently a carbocycle or a heterocycle optionally substituted with 1 to 3 RZ groups; each RZ is independently F, Cl, Br, I, OH, —CN, —N3, —NO2, —OR, —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, (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; wherein each alkyl, alkenyl, alkynyl, aryl, heterocyclyl, or arylalkyl is independently optionally substituted with one or more Z groups; 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; wherein each alkyl, alkenyl, alkynyl, aryl, heterocyclyl, or arylalkyl is independently optionally substituted with one or more Z groups; each X1 or X2 is independently C—R10 or N; each R8 is halogen, NR11R12, N(R11)OR11, NR11NR11R12, N3, NO, NO2, CHO, CN, —CH(═NR11), —CN═NHNR11, —CN═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; wherein each aryl or heteroaryl is independently optionally substituted with one or more Z groups; each R9 or R10 is independently H, halogen, NR11R12, N(R11)OR11, NR11NR11R12, N3, NO, NO2, CHO, CN, —CH(═NR11), —CN═NHNR11, —CN═N(OR11), —CH(OR11)2, —C(═O)NR11R12, —C(═S)NR11R12, —C(═O)OR11, R11, OR11 or SR11; each R11 or R12 is 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; wherein each aryl or heteroaryl is independently optionally substituted with one or more Z groups; or R11 and R12 taken together with a nitrogen to which they are both attached 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—; each Z is independently halogen, —O−, ═O, —ORb, —SRb, —S−, —NRb 2, —N+Rb 3, ═NRb, —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO2, ═N2, —N3, —NHC(═O)Rb, —OC(═O)Rb, —NHC(═O)NRb 2, —S(═O)2—, —S(═O)2OH, —S(═O)2Rb, —OS(═O)2ORb, —S(═O)2NRb 2, —S(═O)Rb, —OP(═O)(ORb)2, —P(═O)(ORb)2, —P(═O)(O−)2, —P(═O)(OH)2, —P(O)(ORb)(O−), —C(═O)Rb, —C(═O)X, —C(S)Rb, —C(O)ORb, —C(O)O−, —C(S)ORb, —C(O)SRb, —C(S)SRb, —C(O)NRb 2, —C(S)NRb 2, —C(═NRb)NRb 2, where each Rb is independently H, alkyl, aryl, arylalkyl, or heterocycle; wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or aryl(C1-C8)alkyl of each R1, R2, R3, R4, R5, R6, R11 or R12 is, 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. A compound according to claim 1 represented by Formula II wherein X2 is C—R10 and each Y and Y1 is O. 3. A compound according to claim 2 wherein R8 is halogen, NR11R12, N(R11)OR11, NR11NR11R12, OR11 or SR11. 4. A compound according to claim 3 wherein R9 is H or NR11R12. 5. A compound according to claim 4 wherein R7 is H or 6. A compound according to claim 5 wherein R6 is ORa, N3, halogen, CN, methyl, hydroxymethyl, substituted methyl, ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl. 7. A compound according to claim 6 wherein X2 is C—H and R3 and R5 are each H. 8. A compound according to claim 7 wherein at least one of R2 or R4 is ORa. 9. A compound according to claim 8 wherein X1 is N or C—R10 wherein R10 is H, halogen, CN or optionally substituted heteroaryl. 10. A compound according claim 9 wherein R2 and R4 are each ORa. 11. A compound according to claim 10 wherein R2 and R4 are OH. 12. A compound according to claim 9 wherein R1 is H, methyl, CH2OH, CH2F, ethenyl, or ethynyl. 13. A compound according to claim 9 wherein X1 is N. 14. A compound according to claim 9 wherein X1 is C—H. 15. A compound according to claim 14 wherein is selected from wherein Y2 is, independently, a bond, O, or CR2. 16. A compound according to claim 9 wherein W1 and W2 are each, independently, a group of the Formula Ia. 17. A compound according to claim 9 wherein R7 is H. 18. A compound that is or a pharmaceutically acceptable salt thereof. 19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. 20. The pharmaceutical composition of claim 19 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, alpha-glucosidase 1 inhibitors, cyclophilin inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV. 21. A method of inhibiting HCV polymerase comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1. 22. 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. 23. The method of claim 22 wherein the viral infection is caused by Hepatitis C virus. 24. The method of claim 23 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 I inhibitors, cyclophilin inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV.