Claims for Patent: 8,318,682

Summary for Patent: 8,318,682

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 with a cyano group. The compounds, compositions, and methods provided are useful for the treatment of Flaviviridae virus infections, particularly hepatitis C infections.
Inventor(s):	Butler; Thomas (Redwood City, CA), Cho; Aesop (Mountain View, CA), Kim; Choung U. (San Carlos, CA), Parrish; Jay P. (Redwood City, CA), Saunders; Oliver L. (San Mateo, CA), Zhang; Lijun (Los Altos Hills, CA)
Assignee:	Gilead Sciences, Inc. (Foster City, CA)
Application Number:	13/196,117
Patent Claims:	1. A compound of Formula I: ##STR00405## or a pharmaceutically acceptable salt, thereof; wherein: each R.sup.1, R.sup.2, R.sup.3, R.sup.4, or R.sup.5 is independently H, OR.sup.a, N(R.sup.a).sub.2, N.sub.3, CN, NO.sub.2, S(O).sub.nR.sup.a, halogen, (C.sub.1-C.sub.8)alkyl, (C.sub.4-C.sub.8)carbocyclylalkyl, (C.sub.1-C.sub.8) substituted alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8) substituted alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.2-C.sub.8) substituted alkynyl, or aryl(C.sub.1-C.sub.8)alkyl; or any two R.sup.1, R.sup.2, R.sup.3, R.sup.4, or R.sup.5 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; R.sup.6 is CN; each n is independently 0, 1, or 2; each R.sup.a is independently H, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl, (C.sub.4-C.sub.8)carbocyclylalkyl, --C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.11, --C(.dbd.O)NR.sup.11R.sup.12, --C(.dbd.O)SR.sup.11, --S(O)R.sup.11, --S(O).sub.2R.sup.11, --S(O)(OR.sup.11), --S(O).sub.2(OR.sup.11), or --SO.sub.2NR.sup.11R.sup.12; R.sup.7 is H, --C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.11, --C(.dbd.O)NR.sup.11R.sup.12, --C(.dbd.O)SR.sup.11, --S(O)R.sup.11, --S(O).sub.2R.sup.11, --S(O)(OR.sup.11), --S(O).sub.2(OR.sup.11), --SO.sub.2NR.sup.11R.sup.12, or ##STR00406## Y is O, S, NR, .sup.+N(O)(R), N(OR), .sup.+N(O)(OR), or N--NR.sub.2; W.sup.1 and W.sup.2, when taken together, are --Y.sup.3(C(R.sup.y).sub.2).sub.3Y.sup.3--; or one of W.sup.1 or W.sup.2 together with either R.sup.3 or R.sup.4 is --Y.sup.3-- and the other of W.sup.1 or W.sup.2 is Formula Ia; or W.sup.1 and W.sup.2 are each, independently, a group of the Formula Ia: ##STR00407## wherein: each Y.sup.1 is, independently, O, S, NR, .sup.+N(O)(R), N(OR), .sup.+N(O)(OR), or N--NR.sub.2; each Y.sup.2 is independently a bond, O, CR.sub.2, NR, .sup.+N(O)(R), N(OR), .sup.+N(O)(OR), N--NR.sub.2, S, S--S, S(O), or S(O).sub.2; each Y.sup.3 is independently O, S, or NR; M2 is 0, 1 or 2; each R.sup.x is a group of the formula: ##STR00408## 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 R.sup.7 is independently H, F, Cl, Br, I, OH, --CN, --N.sub.3, --NO.sub.2, --OR, --C(.dbd.Y.sup.1)R, --C(Y.sup.1)W.sup.5, --C(.dbd.Y.sup.1)OR, --C(.dbd.Y.sup.1)N(R).sub.2, --N(R).sub.2, --.sup.+N(R).sub.3, --SR, --S(O)R, --S(O).sub.2R, --SO.sub.2W.sup.5, --S(O)(OR), --S(O).sub.2(OR), --OC(.dbd.Y.sup.1)R, --OC(.dbd.Y.sup.1)OR, --OC(.dbd.Y.sup.1)(N(R).sub.2), --SC(.dbd.Y.sup.1)R, --SC(.dbd.Y.sup.1)OR, --SC(.dbd.Y.sup.1)(N(R).sub.2), --N(R)C(.dbd.Y.sup.1)R, --N(R)C(.dbd.Y.sup.1)OR, --N(R)C(.dbd.Y.sup.1)N(R).sub.2, --SO.sub.2NR.sub.2, W.sup.5, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) substituted alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8) substituted alkenyl, (C.sub.2-C.sub.8) alkynyl, (C.sub.2-C.sub.8) substituted alkynyl, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heterocyclyl, C.sub.2-C.sub.20 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 R.sup.y on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms; each W.sup.5 is independently a carbocycle or a heterocycle optionally substituted with 1 to 3 R.sup.z groups; each R.sup.z is independently F, Cl, Br, I, OH, --CN, --N.sub.3, --NO.sub.2, --OR, --C(.dbd.Y.sup.1)R, --C(.dbd.Y.sup.1)OR, --C(.dbd.Y.sup.1)N(R).sub.2, --N(R).sub.2, --.sup.+N(R).sub.3, --SR, --S(O)R, --S(O).sub.2R, --S(O)(OR), --S(O).sub.2(OR), --OC(.dbd.Y.sup.1)R, --OC(.dbd.Y.sup.1)OR, --OC(.dbd.Y.sup.1)(N(R).sub.2), --SC(.dbd.Y.sup.1)R, --SC(.dbd.Y.sup.1)OR, --SC(.dbd.Y.sup.1)(N(R).sub.2), --N(R)C(.dbd.Y.sup.1)R, --N(R)C(.dbd.Y.sup.1)OR, --N(R)C(.dbd.Y.sup.1)N(R).sub.2, --SO.sub.2NR.sub.2, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) substituted alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8) substituted alkenyl, (C.sub.2-C.sub.8) alkynyl, (C.sub.2-C.sub.8) substituted alkynyl, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heterocyclyl, C.sub.2-C.sub.20 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, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) substituted alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8) substituted alkenyl, (C.sub.2-C.sub.8) alkynyl, (C.sub.2-C.sub.8) substituted alkynyl, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heterocyclyl, C.sub.2-C.sub.20 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 X.sup.1 or X.sup.2 is independently C--R.sup.10 or N; each R.sup.8 is halogen, NR.sup.11R.sup.12, N(R.sup.11)OR.sup.11, NR.sup.11NR.sup.11R.sup.12, N.sub.3, NO, NO.sub.2, CHO, CN, --CH(.dbd.NR.sup.11), --CH.dbd.NHNR.sup.11, --CH.dbd.N(OR.sup.11), --CH(OR.sup.11).sub.2, --C(.dbd.O)NR.sup.11R.sup.12, C(.dbd.S)NR.sup.11R.sup.12, --C(.dbd.O)OR.sup.11, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.4-C.sub.8)carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, --C(.dbd.O)(C.sub.1-C.sub.8)alkyl, --S(O).sub.n(C.sub.1-C.sub.8)alkyl, aryl(C.sub.1-C.sub.8)alkyl, OR.sup.11 or SR.sup.11; wherein each aryl or heteroaryl is independently optionally substituted with one or more Z groups; each R.sup.9 or R.sup.10 is independently H, halogen, NR.sup.11R.sup.12, N(R.sup.11)OR.sup.11, NR.sup.11NR.sup.11R.sup.12, N.sub.3, NO, NO.sub.2, CHO, CN, --CH(.dbd.NR.sup.11), --CH.dbd.NHNR.sup.11, --CH.dbd.N(OR.sup.11), --CH(OR.sup.11).sub.2, --C(.dbd.O)NR.sup.11R.sup.12, --C(.dbd.S)NR.sup.11R.sup.12, --C(.dbd.O)OR.sup.11, R.sup.11, OR.sup.11 or SR.sup.11; each R.sup.11 or R.sup.12 is independently H, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.4-C.sub.8)carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, --C(.dbd.O)(C.sub.1-C.sub.8)alkyl, --S(O).sub.n(C.sub.1-C.sub.8)alkyl or aryl(C.sub.1-C.sub.8)alkyl; wherein each aryl or heteroaryl is independently optionally substituted with one or more Z groups; or R.sup.11 and R.sup.12 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 --NR.sup.a--; each Z is independently halogen, --O.sup.-, .dbd.O, --OR.sup.b, --SR.sup.b, --S.sup.-, --NR.sup.b.sub.2, --N.sup.+R.sup.b.sub.3, .dbd.NR.sup.b, --CN, --OCN, --SCN, --N.dbd.C.dbd.O, --NCS, --NO, --NO.sub.2, .dbd.N.sub.2, --N.sub.3, --NHC(.dbd.O)R.sup.b, --OC(.dbd.O)R.sup.b, --NHC(.dbd.O)NR.sup.b.sub.2, --S(.dbd.O).sub.2--, --S(.dbd.O).sub.2OH, --S(.dbd.O).sub.2R.sup.b, --OS(.dbd.O).sub.2OR.sup.b, --S(.dbd.O).sub.2NR.sup.b.sub.2, --S(.dbd.O)R.sup.b, --OP(.dbd.O)(OR.sup.b).sub.2, --P(.dbd.O)(OR.sup.b).sub.2, --P(.dbd.O)(O.sup.-).sub.2, --P(.dbd.O)(OH).sub.2, --P(O)(OR.sup.b)(O.sup.-), --C(.dbd.O)R.sup.b, --C(.dbd.O)X, --C(S)R.sup.b, --C(O)OR.sup.b, --C(O)O.sup.-, --C(S)OR.sup.b, --C(O)SR.sup.b, --C(S)SR.sup.b, --C(O)NR.sup.b.sub.2, --C(S)NR.sup.b.sub.2, --C(.dbd.NR.sup.b)NR.sup.b.sub.2, where each R.sup.b is independently H, alkyl, aryl, arylalkyl, or heterocycle; wherein each (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl or aryl(C.sub.1-C.sub.8)alkyl of each R.sup.1, R.sup.2, R.sup.3, R.sup.4, or R.sup.5, R.sup.6 is, independently, optionally substituted with one or more halo, hydroxy, CN, N.sub.3, N(R.sup.a).sub.2 or OR.sup.a; and wherein one or more of the non-terminal carbon atoms of each said (C.sub.1-C.sub.8)alkyl is optionally replaced with --O--, --S-- or --NR.sup.a--. 2. The compound according to claim 1 represented by Formula II ##STR00409## wherein X.sup.2 is C--R.sup.10 and each Y and Y.sup.1 is O. 3. The compound according to claim 2 wherein R.sup.8 is halogen, NR.sup.11R.sup.12, N(R.sup.11)OR.sup.11, NR.sup.11NR.sup.11R.sup.12, OR.sup.11 or SR.sup.11. 4. The compound according to claim 3 wherein R.sup.9 is H or NR.sup.11R.sup.12. 5. The compound according to claim 4 wherein R.sup.7 is H or ##STR00410## 6. The compound according to claim 1 wherein R.sup.5 is N.sub.3. 7. The compound according to claim 6 wherein X.sup.2 is C--H and R.sup.3 and R.sup.5 are each H. 8. The compound according to claim 7 wherein at least one of R.sup.2 or R.sup.4 is OR.sup.a. 9. The compound according to claim 8 wherein X.sup.1 is N or C--R.sup.10 wherein R.sup.10 is H, halogen, CN or optionally substituted heteroaryl. 10. The compound according claim 9 wherein R.sup.2 and R.sup.4 are each OR.sup.a. 11. The compound according to claim 10 wherein R.sup.2 and R.sup.4 are OH. 12. The compound according to claim 9 wherein R.sup.1 is H, methyl, CH.sub.2OH, CH.sub.2F, ethenyl, or ethynyl. 13. The compound according to claim 9 wherein X.sup.1 is N. 14. The compound according to claim 9 wherein X.sup.1 is C--H. 15. The compound according to claim 14 wherein ##STR00411## is selected from ##STR00412## wherein Y.sup.2 is, independently, a bond, O, or CR.sub.2. 16. The compound according to claim 9 wherein W.sup.1 and W.sup.2 are each, independently, a group of the Formula Ia. 17. The compound according to claim 9 wherein R.sup.7 is H. 18. A compound that is ##STR00413## ##STR00414## ##STR00415## 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 1 inhibitors, cyclophilin inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV.