Substituted nucleotide analogs
Disclosed herein are phosphorothioate nucleotide analogs, such as thiophosphoroamidate prodrugs and thiophosphates (including α-thiomonophosphates, α-thiodiphosphates, and α-thiotriphosphates), methods of synthesizing phosphorothioate nucleotide analogs, such as thiophosphoramidate prodrugs, and thiophosphates and methods of treating viral infections, such as HCV, cancer, and/or parasitic diseases with the phosphorothioate nucleotide analogs, such as thiophosphoramidate prodrugs, and thiophosphates.
1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
B 1 is an optionally substituted purine base or an optionally substituted pyrimidine base;
R 1 is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative;
R 2 is an optionally substituted aryl;
R 3a and R 3b are independently hydrogen, deuterium or methyl;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is selected from the group consisting of hydrogen, halogen, —OR 12 and —OC(═O)R 13 ;
R 7 is selected from the group consisting of hydrogen, halogen, —OR 14 and —OC(═O)R 15 ;
or R 6 and R 7 are both oxygen atoms and linked together by a carbonyl group;
R 8 is selected from the group consisting of hydrogen, halogen and an unsubstituted C 1-6 alkyl;
R 9 is hydrogen;
R 12 and R 14 are independently hydrogen or an unsubstituted C 1-6 alkyl; and
R 13 and R 15 are independently an unsubstituted C 1-6 alkyl or an unsubstituted C 3-6 cycloalkyl; and
wherein when a substituent is substituted, the substituent is substituted with a group individually and independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, cycloalkenyl, C 6 -C 10 aryl, 4 to 14 atom heteroaryl, 3 to 18 atom heteroalicyclyl, (aryl)C 1-4 alkyl, (heteroaryl)C 1-4 alkyl, (heteroalicyclyl) C 1-4 alkyl, hydroxy, alkoxy, aryloxy, acyl, cyano, halogen, O-carbamyl, N-carbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfonyl, haloalkyl, haloalkoxy, an amino, a mono-substituted amino group and a di-substituted amino group.
2. The compound of claim 1 , wherein R 8 is an unsubstituted C 1-6 alkyl.
3. The compound of claim 1 , wherein R 8 is methyl.
4. The compound of claim 1 , wherein R 2 is an unsubstituted aryl.
5. The compound of claim 1 , wherein R 2 is an optionally substituted phenyl.
6. The compound of claim 1 , wherein R 1 is an optionally substituted N-linked α-amino acid.
7. The compound of claim 1 , wherein R 1 is an optionally substituted N-linked α-amino acid ester derivative.
8. The compound of claim 1 , wherein R 1 is selected from the group consisting of N-alaninyl, N-asparaginyl, N-aspartatyl, N-cysteinyl, N-glutamatyl, N-glutaminyl, N-glycinyl, N-prolinyl, N-serinyl, N-tyrosinyl, N-argininyl, N-histidinyl, N-isoleucinyl, N-leucinyl, N-lysinyl, N-methioninyl, N-phenylalaninyl, N-threoninyl, tryptophan-tryptophanyl, N-valinyl and ester derivatives thereof.
9. The compound of claim 8 , wherein R 1 is selected from the group consisting of N-alaninyl isopropyl ester, N-alaninyl cyclohexyl ester, N-alaninyl neopentyl ester, N-valinyl isopropyl ester, and N-leucinyl isopropyl ester.
10. The compound of claim 1 , wherein R 1 has the structure
wherein R 22 is selected from the group consisting of hydrogen, an optionally substituted C 1-6 -alkyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C 1-6 alkyl) and an optionally substituted haloalkyl; R 23 is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 1-6 haloalkyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted C 6 aryl, an optionally substituted C 10 aryl and an optionally substituted aryl(C 1-6 alkyl); and R 24 is hydrogen or an optionally substituted C 1-4 -alkyl; or R 23 and R 24 are taken together to form an optionally substituted C 3-6 cycloalkyl.
11. The compound of claim 10 wherein R 23 is an optionally substituted C 1-6 -alkyl.
12. The compound of claim 11 , wherein the optionally substituted C 1-6 -alkyl is methyl.
13. The compound of claim 10 , wherein R 24 is hydrogen.
14. The compound of claim 10 , wherein R 22 is an optionally substituted C 1-6 alkyl or an optionally substituted C 3-6 cycloalkyl.
15. The compound of claim 10 , wherein
16. The compound of claim 15 , wherein
17. The compound of claim 1 , wherein R 6 is —OH or —OC(═O)C 1-6 alkyl; and R 7 is —OH, —OC(═O)C 1-6 alkyl or halogen; or R 6 and R 7 are both oxygen atoms and linked together by a carbonyl group.
18. The compound of claim 1 , wherein B 1 is selected from the group consisting of
wherein R F2 is hydrogen, halogen or methyl; R G2 is an unsubstituted C 1-6 alkyl and R H2 is hydrogen or NH 2 .
19. The compound of claim 18 , wherein B 1 is
20. The compound of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:
or a pharmaceutically acceptable salt of the foregoing.
21. The compound of claim 1 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
22. The compound of claim 21 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 21 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
24. The compound of claim 1 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
25. The compound of claim 24 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
26. The compound of claim 24 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
27. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
28. The compound of claim 1 , wherein R 3a and R 3b are both hydrogen.
29. A method for inhibiting replication of a HCV virus comprising contacting a cell infected with the HCV virus with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
30. A method for ameliorating or treating a HCV infection comprising administering to a subject suffering from the HCV infection a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
31. The method claim 30 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
32. The method of claim 31 , further comprising a second agent selected from the group consisting of pegylated interferon-alpha-2a, pegylated interferon-alpha-2b, interferon lambda 1, interferon lambda 2, interferon lambda 3, consensus interferon, ribavirin, cyclosporine A,
or a pharmaceutically acceptable salt of any of the aforementioned compounds.
33. The method of claim 32 , wherein the second agent is
or a pharmaceutically acceptable salt thereof.
34. The method of claim 32 , wherein the second agent is
or a pharmaceutically acceptable salt thereof.
35. The method of claim 32 , wherein the second agent is ribavirin.
36. The method of claim 30 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
37. The method of claim 30 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
38. The method of claim 30 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
39. The method of claim 30 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
40. A compound of Formula (I), or a 5′-thio-monophosphate thereof, or a pharmaceutically acceptable salt of the foregoing:
wherein:
B 1 is an optionally substituted purine base or an optionally substituted pyrimidine base;
R 1 is O − or OH;
R 2 is hydrogen, absent or
wherein R 19 , R 20 and R 21 are independently absent or hydrogen, and n is 0 or 1;
R 3a and R 3b are independently hydrogen, deuterium or methyl;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is selected from the group consisting of hydrogen, halogen, —OR 12 and —OC(═O)R 13 ;
R 7 is selected from the group consisting of hydrogen, halogen, —OR 14 and —OC(═O)R 15 ;
or R 6 and R 7 are both oxygen atoms and linked together by a carbonyl group;
R 8 is halogen or unsubstituted C 1-6 alkyl;
R 9 is hydrogen;
R 12 and R 14 are independently hydrogen or an unsubstituted C 1-6 alkyl; and
R 13 and R 15 are independently an unsubstituted C 1-6 alkyl or an unsubstituted C 3-6 cycloalkyl;
wherein when a substituent is substituted, the substituent is substituted with a group individually and independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, cycloalkenyl, C 6 -C 10 aryl, 4 to 14 atom heteroaryl, 3 to 18 atom heteroalicyclyl, (aryl)C 1-4 alkyl, (heteroaryl)C 1-4 alkyl, (heteroalicyclyl) C 1-4 alkyl, hydroxy, alkoxy, aryloxy, acyl, cyano, halogen, O-carbamyl, N-carbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfonyl, haloalkyl, haloalkoxy, an amino, a mono-substituted amino group and a di-substituted amino group.
41. The compound of claim 40 , wherein R 8 is an unsubstituted C 1-6 alkyl.
42. The compound of claim 41 , wherein R 8 is methyl.
43. The compound of claim 40 , wherein n is 1.
44. The compound of claim 40 , wherein n is 0.
45. The compound of claim 40 , wherein R 6 is —OH or —OC(═O)C 1-6 alkyl; and R 7 is —OH or —OC(═O)C 1-6 alkyl; or R 6 and R 7 are both oxygen atoms and linked together by a carbonyl group.
46. The compound of claim 40 , wherein B 1 is selected from the group consisting of
wherein R F2 is hydrogen, halogen or methyl; R G2 is an unsubstituted C 1-6 alkyl and R H2 is hydrogen or NH 2 .
47. The compound of claim 46 , wherein B 1 is
48. The compound of claim 40 , wherein the compound of Formula (I) is selected from the group consisting of:
49. The compound of claim 48 , wherein the compound of Formula (I) is:
50. The compound of claim 48 , wherein the compound of Formula (I) is:
51. The compound of claim 48 , wherein the compound of Formula (I) is:
52. The compound of claim 48 , wherein the compound of Formula (I) is:
53. The compound of claim 40 , wherein R 3a and R 3b are both hydrogen.
54. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 40 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
55. A method for ameliorating or treating a HCV viral infection comprising contacting a cell infected with HCV with an effective amount of a compound of claim 40 , or a pharmaceutically acceptable salt thereof.
56. A method for inhibiting replication of a HCV virus comprising contacting a cell infected with the HCV virus with an effective amount of a compound of claim 40 , or a pharmaceutically acceptable salt thereof.
57. The method of claim 56 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
58. The method of claim 57 , further comprising a second agent selected from the group consisting of pegylated interferon-alpha-2a, pegylated interferon-alpha-2b, interferon lambda 1, interferon lambda 2, interferon lambda 3, consensus interferon, ribavirin, cyclosporine A,
or a pharmaceutically acceptable salt of any of the aforementioned compounds.
59. The method of claim 58 , wherein the second agent is
or a pharmaceutically acceptable, salt thereof.
60. The method of claim 58 , wherein the second agent is
or a pharmaceutically acceptable salt thereof.
61. The method of claim 58 , wherein the second agent is ribavirin.
62. The method of claim 56 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
63. The method of claim 56 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
64. The method of claim 56 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
65. The method of claim 56 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.