IP Library › Granted Patent US 10,307,439

Granted Patent B2

US 10,307,439 · App. 15/423,270 · Granted Jun 4, 2019

Substituted nucleosides, nucleotides and analogs thereof

Inventors: Lawrence M. Blatt (Healdsburg, CA); Leonid Beigelman (San Mateo, CA); Julian Alexander Symons (San Carlos, CA); David Bernard Smith (San Mateo, CA)

Assignee: Alios Biopharma, Inc.

A61K31/708 A61K31/7068 A61K31/7072 A61K31/7076 A61K45/06 C07F9/65586 C07F9/65742

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Quick Facts

Patent No.: US 10,307,439
App. No.: 15/423,270
Granted: Jun 4, 2019
Kind: B2

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Abstract

Disclosed herein are nucleosides, nucleotides and nucleotide analogs, methods of synthesizing the same and methods of treating diseases and/or conditions such as a Coronaviridae virus, a Togaviridae virus, a Hepeviridae virus and/or a Bunyaviridae virus infection with one or more nucleosides, nucleotides and nucleotide analogs.

Claims (162)

1. A method for ameliorating or treating a betacoronavirus infection comprising contacting a cell infected with the betacoronavirus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure:

wherein:

B 1A is

wherein R G2 is an unsubstituted C 1-6 alkyl;

R 3A is halo, OH, —OC(═O)R″ A or an unsubstituted O-linked α-amino acid;

R 4A is OH or halo;

R a1 and R a2 are independently hydrogen or deuterium;

R A is hydrogen or deuterium;

R 1A is selected from the group consisting of hydrogen,

R 2A is halo or —(CH 2 ) 1-6 halogen;

R 5A is selected from the group consisting of an unsubstituted C 1-6 alkyl, an unsubstituted C 2-6 alkenyl and an unsubstituted C 2-6 alkynyl;

R 6A and R 7A are independently selected from the group consisting of absent, hydrogen and

R 6A is

and R 7A is absent or hydrogen;

R 8A is an absent, hydrogen, an optionally substituted phenyl or an optionally substituted naphthyl;

R 9A is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative, wherein the main-chain carboxylic acid group has been converted to an ester group;

R 10A and R 11A are independently an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative, wherein the main-chain carboxylic acid group has been converted to an ester group;

R 12A and R 13A are independently absent or hydrogen;

R 14A is O − or OH;

R 22A and R 23A are each hydrogen;

R 24A is selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted —O—C 1-24 alkyl;

m is 0 or 1;

s is 0, 1, 2 or 3; and

Z 1A , Z 2A , Z 3A and Z 4A are each O; and

wherein when a group is substituted, the group is substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, -thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.

2. The method of claim 1 , wherein the cell is in a human subject.

3. The method of claim 1 , wherein the betacoronavirus is MERS-CoV.

4. The method of claim 1 , wherein the betacoronavirus is SARS-CoV.

5. The method of claim 1 , wherein R 2A is F.

6. The method of claim 1 , wherein R 2A is —(CH 2 ) 1-6 F.

7. The method of claim 6 , wherein R 2A is —CH 2 ) F.

8. The method of claim 1 , wherein R 3A is OH.

9. The method of claim 1 , wherein R 3A is F.

10. The method of claim 1 , wherein R 4A is OH.

11. The method of claim 1 , wherein R 4A is F.

12. The method of claim 1 , wherein R 5A is methyl.

13. The method of claim 1 , wherein R 5A is ethynyl.

14. The method of claim 1 , wherein B 1A is

wherein R G2 is CH 2 CH 3 ; R a1 and R a2 are each hydrogen; R A is hydrogen; R 2A is F or CH 2 F; R 3A is OH or F; R 4A is OH or F; and R 5A is methyl or ethynyl.

15. The method of claim 1 , wherein B 1A is

wherein R G2 is CH 2 CH 3 ; R a1 and R a2 are each hydrogen; R A is hydrogen; R 2A is F; R 3A is OH; R 4A is F; and R 5A is methyl.

16. The method of claim 1 , wherein B 1A is

wherein R G2 is CH 2 CH 3 ; R a1 and R a2 are each hydrogen; R A is hydrogen; R 2A is F; R 3A is F; R 4A is OH; and R 5A is methyl.

17. The method of claim 1 , wherein R 1A is hydrogen.

18. The method of claim 1 , wherein R 1A is

19. The method of claim 18 , wherein R 6A is absent or hydrogen; and R 7A is absent or hydrogen.

20. The method of claim 18 , wherein R 6A and R 7A are independently

s is 0; and R 24A is an unsubstituted C 1-4 alkyl or an unsubstituted —O—C 1-4 alkyl.

21. The method of claim 18 , wherein R 6A is

m is 0, and R 7A , R 12A and R 13A are independently absent or hydrogen.

22. The method of claim 18 , wherein R 6A is

m is 1,R 7A , R 12A and R 13A are independently absent or hydrogen; and R 14A is O − or OH.

23. The method of claim 1 , wherein R 1A is

24. The method of claim 23 , wherein R 8A is an optionally substituted phenyl or an optionally substituted naphthyl; and R 9A is an optionally substituted N-linked α-amino acid selected from the group consisting of N-linked alanine, N-linked glycine, N-linked valine and N-linked leucine, or an optionally substituted N-linked α-amino acid ester derivative, wherein the N-linked α-amino acid is selected from the group consisting of N-linked alanine, N-linked glycine, N-linked valine and N-linked leucine, and the ester is selected from the group consisting of alkyl ester, cycloalkyl ester, an optionally substituted phenyl ester and an optionally substituted benzyl ester.

25. The method of claim 24 , wherein R 8A is an optionally substituted phenyl or an optionally substituted naphthyl; and R 9A is selected from the group consisting of N-linked alanine, N-linked alanine isopropyl ester, N-linked alanine cyclohexyl ester and N-linked alanine neopentyl ester.

26. The method of claim 1 , wherein B 1A is

27. The method of claim 1 , wherein B 1A is

wherein R G2 is —CH 2 CH 3 .

28. The method of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing.

29. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing.

30. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing.

31. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing.

32. A method for ameliorating or treating a MERS viral infection comprising contacting a cell infected with the MERS virus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure:

wherein:

B 1A is

wherein R G2 is an unsubstituted C 1-6 alkyl;

R 3A is halo, OH, —OC(═O)R″ A or an unsubstituted O-linked α-amino acid;

R 4A is OH or halo;

R a1 and R a2 are independently hydrogen or deuterium;

R A is hydrogen or deuterium;

R 1A is selected from the group consisting of hydrogen,

R 2A is halo or —(CH 2 ) 1-6 halogen;

R 5A is selected from the group consisting of an unsubstituted C 1-6 alkyl, an unsubstituted C 2-6 alkenyl and an unsubstituted C 2-6 alkynyl;

R 6A and R 7A are independently selected from the group consisting of absent, hydrogen and

R 6A is

and R 7A is absent or hydrogen;

R 8A is an optionally substituted phenyl or an optionally substituted naphthyl;

R 10A and R 11A are independently an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative;

R 12A and R 13A are independently absent or hydrogen;

R 14A is O − or OH;

R 22A and R 23A are each hydrogen;

R 24A is selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted —O—C 1-24 alkyl;

m is 0 or 1;

s is 0, 1, 2 or 3; and

Z 1A , Z 2A , Z 3A and Z 4A are O; and

wherein when a group is substituted, the group is substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.

33. The method of claim 32 , wherein the cell is in a human subject.

34. The method of claim 32 , wherein B 1A is

35. The method of claim 32 , wherein B 1A is

wherein R G2 is —CH 2 CH 3 .

36. The method of claim 32 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the forgoing.

37. The method of claim 18 , wherein R 6A and R 7A are each isopropyloxycarbonyloxymethyl.

38. The method of claim 23 , wherein R 8A is an unsubstituted phenyl.

39. The method of claim 38 , wherein R 9A is an unsubstituted C 1-6 alkyl ester or an unsubstituted C 3-6 cycloalkyl ester of an N-linked α-amino acid selected from the group consisting of N-linked alanine, N-linked isoleucine, N-linked leucine and N-linked valine.

40. The method of claim 38 , wherein R 9A is selected from the group consisting of

41. The method of claim 1 , wherein:

R 2A is F;

R 3A is OH or F;

R 4A is OH or F; and

R 5A is methyl or ethynyl.

42. The method of claim 32 , wherein:

R 2A is F;

R 3A is OH or F;

R 4A is OH or F; and

R 5A is methyl or ethynyl.

43. The method of claim 32 , wherein B 1A is

wherein R G2 is CH 2 CH 3 ; R a1 and R a2 are each hydrogen; R A is hydrogen; R 2A is F or CH 2 F; R 3A is OH or F; R 4A is OH or F; and R 5A is methyl or ethynyl.

44. The method of claim 39 , wherein B 1A is

wherein R G2 is CH 2 CH 3 ; R a1 and R a2 are each hydrogen; R A is hydrogen; R 2A is F; R 3A is OH; R 4A is F; and R 5A is methyl.

45. The method of claim 39 , wherein B 1A is

wherein R G2 is CH 2 CH 3 ; R a1 and R a2 are each hydrogen; R A is hydrogen; R 2A is F; R 3A is F; R 4A is OH; and R 5A is methyl.

46. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof, wherein B 1A is

R G2 is —CH 2 CH 3 ; and R 1A is hydrogen.

47. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof, wherein B 1A is

R G2 is —CH 2 CH 3 ; and R 1A is hydrogen.

48. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof, wherein B 1A is

R G2 is —CH 2 CH 3 ; and R 1A is hydrogen.

49. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof, wherein B 1A is

R G2 is —CH 2 CH 3 ; and R 1A is hydrogen.

50. The method of claim 1 , wherein the compound is