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):	Butler; Thomas (Carmel, CA), Cho; Aesop (Mountain View, CA), Kim; Choung U. (San Carlos, CA), Parrish; Jay P. (El Dorado Hills, CA), Saunders; Oliver L. (Clovis, CA), Zhang; Lijun (Los Altos Hills, CA)
Assignee:	GILEAD SCIENCES, INC (Foster City, CA)
Application Number:	15/288,271
Patent Claims:	1. A compound of Formula II: ##STR00406## or a pharmaceutically acceptable salt, thereof; wherein: R.sup.1, R.sup.3, and R.sup.5 are H; R.sup.2 and R.sup.4 are, independently, OR.sup.a; R.sup.6 is OR.sup.a, N.sub.3, CN, S(O).sub.nR.sup.a, --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, halogen, substituted methyl, ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl; 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 ##STR00407## 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 W.sup.1 and W.sup.2 are each, independently, a group of the Formula Ia: ##STR00408## Y and each Y.sup.1 are independently O, S, NR, .[..sup.+N(O)(R).]. .Iadd..sup.+N(O.sup.-)(R).Iaddend., N(OR), .[..sup.+N(O)(OR).]. .Iadd..sup.+N(O.sup.-)(OR).Iaddend., or N--NR.sub.2; each Y.sup.2 is independently a bond, O, CR.sub.2, NR, .[..sup.+N(O)(R).]. .Iadd..sup.+N(O.sup.-)(R).Iaddend., N(OR), .[..sup.+N(O)(OR).]. .Iadd..sup.+N(O.sup.-)(OR).Iaddend., 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 independently R.sup.y or the formula: ##STR00409## 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.y is independently H, F, Cl, Br, I, OH, R, --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, .[.--+N(R).sub.3.]. .Iadd.--.sup.+N(R).sub.3.Iaddend., --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, --CN, --N.sub.3, --NO.sub.2, --OR, or W.sup.3; or when taken together, two R.sup.y on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms; 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; W.sup.3 is W.sup.4 or W.sup.5; W.sup.4 is R, --C(Y.sup.1)R.sup.y, --C(Y.sup.1)W.sup.5, --SO.sub.2R.sup.y, or --SO.sub.2W.sup.5; and W.sup.5 is a carbocycle or a heterocycle wherein W.sup.5 is independently substituted with 0 to 3 R.sup.y groups; X.sup.2 is C--R.sup.10 and X.sup.1 is C--R.sup.10 or N; 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.nC.sub.1-C.sub.8)alkyl.]. .Iadd.--S(O).sub.n(C.sub.1-C.sub.8)alkyl.Iaddend., aryl(C.sub.1-C.sub.8)alkyl, OR.sup.11 or SR.sup.11; R.sup.9 and each R.sup.10 are 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 and each R.sup.12 are 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; or R.sup.11 and R.sup.12 taken together with a nitrogen to which they are both attached .Iadd.to .Iaddend.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--; wherein substituted methyl, substituted ethenyl and substituted ethynyl of R.sup.6 and 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 of R.sup.11 and R.sup.12 are 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, wherein R.sup.6 is OR.sup.a, N.sub.3, halogen, CN, substituted methyl, ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl. 3. The compound according to claim 1, wherein R.sup.2 and R.sup.4 are OH. 4. The compound according to claim 2, wherein R.sup.2 and R.sup.4 are OH. 5. The compound according to claim 1, wherein R.sup.6 is CN. 6. The compound according to claim 4, wherein R.sup.6 is CN. 7. The compound according to claim 4, wherein R.sup.9 is NR.sup.11R.sup.12. 8. The compound according to claim 7, wherein X.sup.2 is C--H. 9. The compound according to claim 8, wherein X.sup.1 is C--H. 10. The compound according to claim 9, wherein R.sup.7 is H. 11. The compound according to claim 9, wherein ##STR00410## 12. A compound selected from the group consisting of ##STR00411## 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.]. .Iadd.alpha-glucosidase .Iaddend.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. .Iadd.19. The method of claim 16, wherein the viral infection is caused by Zika virus. .Iaddend. .Iadd.20. A compound of ##STR00412## or a pharmaceutically acceptable salt, thereof; wherein: R.sup.1, R.sup.3, and R.sup.5 are H; R.sup.2 and R.sup.4 are OH; R.sup.6 is CN; 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 ##STR00413## 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 W.sup.1 and W.sup.2 are each, independently, a group of the Formula Ia: ##STR00414## Y and each Y.sup.1 are O, S, NR, .sup.+N(O.sup.-)(R), N(OR), .sup.+N(O.sup.-)(OR), or N--NR.sub.2; each Y.sup.2 is independently a bond, O, CR.sub.2, NR, .sup.+N(O.sup.-)(R), N(OR), .sup.+N(O.sup.-)(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 independently R.sup.y or the formula: ##STR00415## 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.y is independently H, F, Cl, Br, I, OH, R, --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, --CN, --N.sub.3, --NO.sub.2, --OR, or W.sup.3; or when taken together, two R.sup.y on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms; 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) alkenyl, (C.sub.2-C.sub.8) substituted alkenyl, 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; W.sup.3 is W.sup.4 or W.sup.5; W.sup.4 is R, --C(Y.sup.1)R.sup.y, --C(Y.sup.1)W.sup.5, --SO.sub.2R.sup.y, or --SO.sub.2W.sup.5; and W.sup.5 is a carbocycle or a heterocycle wherein W.sup.5 is independently substituted with 0 to 3 R.sup.y groups; X.sup.2 is C--H and X.sup.1 is C--H; 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; R.sup.9 is 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 and each R.sup.12 are 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; or R.sup.11 and R.sup.12 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 --NR.sup.a--; 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 of R.sup.11 and R.sup.12 are 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--. .Iaddend. .Iadd.21. The compound of claim 20, wherein ##STR00416## is selected from ##STR00417## wherein Y.sup.2 is, independently, a bond, O, or CR.sub.2. .Iaddend. .Iadd.22. The compound of claim 20, wherein W.sup.1 and W.sup.2 are each, independently, a group of the Formula Ia. .Iaddend. .Iadd.23. A pharmaceutical composition comprising the compound of claim 20. .Iaddend. .Iadd.24. A method of treating a Flaviviridae viral infection in a human in need thereof by administering the compound of claim 20. .Iaddend. .Iadd.25. The method of treating a Flaviviridae viral infection of claim 24 wherein the Flaviviridae viral infection is caused by a Zika virus. .Iaddend. .Iadd.26. A method of treating a Flaviviridae viral infection by contacting a cell with the compound of claim 20. .Iaddend. .Iadd.27. The method of treating a Flaviviridae viral infection of claim 26 wherein the Flaviviridae viral infection is caused by a Zika virus. .Iaddend. .Iadd.28. A compound:.Iaddend. ##STR00418## .Iadd.29. A pharmaceutical composition comprising the compound of claim 28. .Iaddend. .Iadd.30. A method of treating a Flaviviridae viral infection in a human in need thereof by administering the compound of claim 28. .Iaddend. .Iadd.31. The method of treating a Flaviviridae viral infection of claim 30 wherein the Flaviviridae viral infection is caused by a Zika virus. .Iaddend. .Iadd.32. A method of treating a Flaviviridae viral infection by contacting a cell with the compound of claim 28. .Iaddend. .Iadd.33. The method of treating a Flaviviridae viral infection of claim 32 wherein the Flaviviridae viral infection is caused by a Zika virus. .Iaddend.