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Last Updated: October 28, 2020

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Claims for Patent: 9,422,322

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Summary for Patent: 9,422,322
Title:Substituted nucleosides, nucleotides and analogs thereof
Abstract: Disclosed herein are nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of nucleosides, nucleotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a paramyxovirus viral infection, with a nucleoside, a nucleotide and an analog thereof.
Inventor(s): Dyatkina; Natalia (Mountain View, CA), Wang; Guangyi (Carlsbad, CA), Beigelman; Leonid (San Mateo, CA), Rajwanshi; Vivek Kumar (Cupertino, CA)
Assignee: Alios BioPharma, Inc. (South San Francisco, CA)
Application Number:14/312,990
Patent Claims:1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, ##STR00129## wherein: B.sup.1A is an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R.sup.A is hydrogen or deuterium; R.sup.1A is selected from the group consisting of hydrogen, an optionally substituted acyl, an optionally substituted O-linked amino acid, ##STR00130## R.sup.a1 and R.sup.a2 are independently hydrogen or deuterium; R.sup.2A is a C.sub.1-6 azidoalkyl; R.sup.3A is selected from the group consisting of OH, --OC(.dbd.O)R''.sup.A and an optionally substituted O-linked amino acid; R.sup.4A is halogen; R.sup.5A is hydrogen or halogen; R.sup.6A, R.sup.7A and R.sup.8A are independently selected from the group consisting of absent, hydrogen, an optionally substituted C.sub.1-24 alkyl, an optionally substituted C.sub.3-24 alkenyl, an optionally substituted C.sub.3-24 alkynyl, an optionally substituted C.sub.3-6 cycloalkyl, an optionally substituted C.sub.3-6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aryl(C.sub.1-6 alkyl), an optionally substituted *--(CR.sup.15AR.sup.16A).sub.p--O--C.sub.1-24 alkyl, an optionally substituted *--(CR.sup.17AR.sup.18A).sub.q--O--C.sub.1-24 alkenyl, ##STR00131## or R.sup.6A is ##STR00132## and R.sup.7A is absent or hydrogen; or R.sup.6A and R.sup.7A are taken together to form a moiety selected from the group consisting of an optionally substituted ##STR00133## and an optionally substituted ##STR00134## wherein the oxygens connected to R.sup.6A and R.sup.7A, the phosphorus and the moiety form a six-membered to ten-membered ring system; R.sup.9A is independently selected from the group consisting of an optionally substituted C.sub.1-24 alkyl, an optionally substituted C.sub.2-24 alkenyl, an optionally substituted C.sub.2-24 alkynyl, an optionally substituted C.sub.3-6 cycloalkyl, an optionally substituted C.sub.3-6 cycloalkenyl, NR.sup.30AR.sup.31A, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; R.sup.10A and R.sup.11A are independently an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; R.sup.12A, R.sup.13A and R.sup.14A are independently absent or hydrogen; each R.sup.15A, each R.sup.16A, each R.sup.17A and each R.sup.18A are independently hydrogen, an optionally substituted C.sub.1-24 alkyl or alkoxy; R.sup.19A, R.sup.20A, R.sup.22A and R.sup.23A are independently selected from the group consisting of hydrogen, an optionally substituted C.sub.1-24 alkyl and an optionally substituted aryl; R.sup.21A and R.sup.24A are independently selected from the group consisting of hydrogen, an optionally substituted C.sub.1-24 alkyl, an optionally substituted aryl, an optionally substituted --O--C.sub.1-24 alkyl, an optionally substituted --O-aryl an optionally substituted --O-heteroaryl, an optionally substituted --O-monocyclic heterocyclyl and ##STR00135## R.sup.25A and R.sup.29A are independently selected from the group consisting of hydrogen, an optionally substituted C.sub.1-24 alkyl and an optionally substituted aryl; R.sup.26A and R.sup.27A are independently --C.ident.N or an optionally substituted substituent selected from the group consisting of C.sub.2-8 organylcarbonyl, C.sub.2-8 alkoxycarbonyl and C.sub.2-8 organylaminocarbonyl; R.sup.28A is selected from the group consisting of hydrogen, an optionally substituted C.sub.1-24-alkyl, an optionally substituted C.sub.2-24 alkenyl, an optionally substituted C.sub.2-24 alkynyl, an optionally substituted C.sub.3-6 cycloalkyl and an optionally substituted C.sub.3-6 cycloalkenyl; R.sup.30A and R.sup.31A are independently selected from the group consisting of hydrogen, an optionally substituted C.sub.1-24-alkyl, an optionally substituted C.sub.2-24 alkenyl, an optionally substituted C.sub.2-24 alkynyl, an optionally substituted C.sub.3-6 cycloalkyl and an optionally substituted C.sub.3-6 cycloalkenyl; R''.sup.A is an optionally substituted C.sub.1-24-alkyl; m and t are independently 0 or 1; p and q are independently selected from the group consisting of 1, 2 and 3; r is 1 or 2; s is 0, 1, 2 or 3; u is 1 or 2; and Z.sup.1A, Z.sup.2A, Z.sup.3A and Z.sup.4A are independently O or S.

2. The compound of claim 1, wherein R.sup.2A is azidomethyl.

3. The compound of claim 1, wherein R.sup.2A is aminomethyl.

4. The compound of claim 1, wherein R.sup.1A is ##STR00136##

5. The compound of claim 4, wherein R.sup.6A and R.sup.7A are both hydrogen or absent.

6. The compound of claim 4, wherein both R.sup.6A and R.sup.7A are independently selected from the group consisting of an optionally substituted C.sub.1-24 alkyl, an optionally substituted C.sub.3-24 alkenyl, an optionally substituted C.sub.3-24 alkynyl, an optionally substituted C.sub.3-6 cycloalkyl, an optionally substituted C.sub.3-6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aryl(C.sub.1-6 alkyl), ##STR00137## or R.sup.6A and R.sup.7A are taken to ether to form a moiety selected from the group consisting of an optionally substituted ##STR00138## and an optionally substituted ##STR00139## wherein the oxygens connected to R.sup.6A and R.sup.7A, the phosphorus and the moiety form a six-membered to ten-membered ring system.

7. The compound of claim 4, wherein R.sup.8A is an optionally substituted aryl; and R.sup.9A is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.

8. The compound of claim 4, wherein R.sup.10A and R.sup.11A are both an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.

9. The compound of claim 1, wherein R.sup.1A is ##STR00140##

10. The compound of claim 9, wherein m is 0, and R.sup.12A and R.sup.13A are independently absent or hydrogen.

11. The compound of claim 9, wherein m is 1, and R.sup.12A, R.sup.13A and R.sup.14A are independently absent or hydrogen.

12. The compound of claim 1, wherein R.sup.1A is H.

13. The compound of claim 1, wherein R.sup.1A is an optionally substituted acyl.

14. The compound of claim 1, wherein R.sup.1A is an optionally substituted O-linked amino acid.

15. The compound of claim 1, wherein B.sup.1A is selected from the group consisting of: ##STR00141## wherein: R.sup.A2 is selected from the group consisting of hydrogen, halogen and NHR.sup.J2, wherein R.sup.J2 is selected from the group consisting of hydrogen, --C(.dbd.O)R.sup.K2 and --C(.dbd.O)OR.sup.L2; R.sup.B2 is halogen or NHR.sup.W2, wherein R.sup.W2 is selected from the group consisting of hydrogen, an optionally substituted C.sub.1-6 alkyl, an optionally substituted C.sub.2-6 alkenyl, an optionally substituted C.sub.3-8 cycloalkyl, --C(.dbd.O)R.sup.M2 and --C(.dbd.O)OR.sup.N2; R.sup.C2 is hydrogen or NHR.sup.O2, wherein R.sup.O2 is selected from the group consisting of hydrogen, --C(.dbd.O)R.sup.P2 and --C(.dbd.O)OR.sup.Q2; R.sup.D2 is selected from the group consisting of hydrogen, deuterium, halogen, an optionally substituted C.sub.1-6 alkyl, an optionally substituted C.sub.2-6 alkenyl and an optionally substituted C.sub.2-6 alkynyl; R.sup.E2 is selected from the group consisting of hydrogen, hydroxy, an optionally substituted C.sub.1-6 alkyl, an optionally substituted C.sub.3-8 cycloalkyl, --C(.dbd.O)R.sup.R2 and --C(.dbd.O)OR.sup.S2; R.sup.F2 is selected from the group consisting of hydrogen, halogen, an optionally substituted C.sub.1-6alkyl, an optionally substituted C.sub.2-6 alkenyl and an optionally substituted C.sub.2-6 alkynyl; Y.sup.2 and Y.sup.3 are independently N or CR.sup.I2, wherein R.sup.I2 is selected from the group consisting of hydrogen, halogen, an optionally substituted C.sub.1-6-alkyl, an optionally substituted C.sub.2-6-alkenyl and an optionally substituted C.sub.2-6-alkynyl; R.sup.G2 is an optionally substituted C.sub.1-6 alkyl; R.sup.H2 is hydrogen or NHR.sup.T2, wherein R.sup.T2 is independently selected from the group consisting of hydrogen, --C(.dbd.O)R.sup.U2 and --C(.dbd.O)OR.sup.V2; and R.sup.K2, R.sup.L2, R.sup.M2, R.sup.N2, R.sup.P2, R.sup.Q2 R.sup.R2, R.sup.S2, R.sup.U2 and R.sup.V2 are independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.6-10 aryl, heteroaryl, heterocyclyl, aryl(C.sub.1-6 alkyl), heteroaryl(C.sub.1-6 alkyl) and heterocyclyl(C.sub.1-6 alkyl).

16. The compound of claim 15, wherein B.sup.1A is ##STR00142##

17. The compound of claim 15, wherein B.sup.1A is ##STR00143##

18. The compound of claim 15, wherein B.sup.1A is ##STR00144##

19. The compound of claim 1, wherein R.sup.3A is OH.

20. The compound of claim 1, wherein R.sup.3A is --OC(.dbd.O)R.sup.''A.

21. The compound of claim 1, wherein R.sup.3A is O-linked amino acid.

22. The compound of claim 1, wherein R.sup.5A is hydrogen.

23. The compound of claim 1, wherein R.sup.4A is fluoro.

24. The compound of claim 1, wherein the compound of Formula (I) is: ##STR00145## or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1, wherein the compound of Formula (I) is: ##STR00146## or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1, wherein the compound of Formula (I) is selected from the group consisting of: ##STR00147## ##STR00148## or a pharmaceutically acceptable salt of the foregoing.

27. The compound of claim 1, wherein the compound of Formula (I) is selected from the group consisting of: ##STR00149## ##STR00150## or a pharmaceutically acceptable salt of the foregoing.

28. The compound of claim 1, wherein the compound of Formula (I) is selected from the group consisting of: ##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155## or a pharmaceutically acceptable salt of the foregoing.

29. A pharmaceutical composition comprising an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

30. A method for ameliorating or treating a paramyxovirus viral infection comprising administering to a subject identified as suffering from the paramyxovirus viral infection an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

31. A method for ameliorating or treating a paramyxovirus viral infection comprising contacting a cell infected with the paramyxovirus in a subject identified as suffering from the viral infection with an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

32. A method for ameliorating or treating a paramyxovirus viral infection in combination with one or more agents comprising administering to or contacting a cell in a subject identified as suffering from the paramyxovirus viral infection with an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

33. The method of claim 31, wherein the paramyxovirus viral infection is a human respiratory syncytial virus infection.

34. The method of claim 32, wherein the paramyxovirus viral infection is a human respiratory syncytial virus infection; and wherein the one or more agents is selected from the group consisting of ribavirin, palivizumab, RSV-IGIV, ALN-RSV01, BMS-433771, RFI-641, RSV604, MDT-637, BTA9881, TMC-353121, MBX-300, YM-53403, RV568 and a RSV-F Particle Vaccine.

35. The compound of claim 1, wherein the compound of Formula (I) is ##STR00156## or a pharmaceutically acceptable salt thereof.

36. The compound of claim 1, wherein the compound of Formula (I) is ##STR00157## or a pharmaceutically acceptable salt thereof.

37. The compound of claim 1, wherein the compound of Formula (I) is ##STR00158## or a pharmaceutically acceptable salt thereof.

38. The compound of claim 1, wherein the compound of Formula (I) is ##STR00159## or a pharmaceutically acceptable salt thereof.

39. The compound of claim 1, wherein the compound of Formula (I) is ##STR00160## or a pharmaceutically acceptable salt thereof.

40. The compound of claim 1, wherein the compound of Formula (I) is ##STR00161## or a pharmaceutically acceptable salt thereof.

41. The compound of claim 1, wherein the compound of Formula (I) is ##STR00162## or a pharmaceutically acceptable salt thereof.

42. The compound of claim 1, wherein the compound of Formula (I) is ##STR00163## or a pharmaceutically acceptable salt thereof.

Details for Patent 9,422,322

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Medimmune SYNAGIS palivizumab VIAL 103770 001 1998-06-19   Start Trial Alios BioPharma, Inc. (South San Francisco, CA) 2039-02-26 RX search
Medimmune SYNAGIS palivizumab VIAL 103770 002 1998-06-19   Start Trial Alios BioPharma, Inc. (South San Francisco, CA) 2039-02-26 RX search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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