2′,4′-fluoro nucleosides for the treatment of HCV
Provided herein are compounds, methods and pharmaceutical compositions for use in treatment of viral infections, including hepatitis C virus (HCV) infections, in hosts in need thereof. In certain embodiments, the compounds are 2′,4′-fluoro nucleosides according to Formula 1001: or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base, R A , and PD are as described herein. In certain embodiments, 2′,4′-fluoro nucleosides are provided which display remarkable efficacy and bioavailability for the treatment of, for example, HCV infection in a human.
1. A compound according to Formula 1001:
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof, wherein:
Base is a nucleobase;
PD is hydrogen,
W is S or O;
each of X and Y is independently hydrogen, —OR 1 , —SR 1 , —NR 1 R 2 , or an N-linked amino acid or ester thereof;
R A is hydrogen, hydroxyl, or halo; or, in the alternative, Y and R A , together with the atoms to which they are attached, combine to form a six-membered heterocyclic ring wherein Y and R A together represent a single divalent —O—, and X is —OR 1 , —SR 1 , —NR 1 R 2 , or an N-linked amino acid or ester thereof;
each R 1 is independently hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aryl, substituted aryl, unsubstituted arylalkyl, substituted arylalkyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted alkylcarbonylthioalkyl or substituted alkylcarbonylthioalkyl; and
each R 2 is independently hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted arylalkyl, or substituted arylalkyl.
2. The compound of claim 1 according to Formula II:
wherein
R A is fluoro or hydroxyl;
Base is
W is S or O;
each of X and Y is independently hydrogen, —OR 1 , —SR 1 , —NR 1 R 2 , or an N-linked amino acid or ester thereof;
R A is hydrogen, hydroxyl, or halo; or, in the alternative, Y and R A , together with the atoms to which they are attached, combine to form a six-membered heterocyclic ring wherein Y and R A together represent a single divalent —O—,
each R 1 is independently hydrogen, unsubstituted alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted alkylcarbonylthioalkyl; and
each R 2 is independently hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, or unsubstituted arylalkyl,
R 4 is hydrogen, hydroxyl, unsubstituted alkoxyl, —NH 2 , or alkyl substituted with an —NH 2 ;
R 5 is hydrogen, hydroxyl, —NH 2 , or unsubstituted alkoxyl;
R 6 is hydrogen, halogen, or unsubstituted alkyl; and
R 7 is hydrogen or —NH 2 ; or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
3. The compound of claim 1 according to Formula III:
wherein
Base is
R 4 is hydrogen, hydroxyl, unsubstituted alkoxyl, —NH 2 , or alkyl substituted with an —NH 2 ;
R 5 is hydrogen, hydroxyl, —NH 2 , or unsubstituted alkoxyl;
R 6 is hydrogen, halogen, or unsubstituted alkyl; and
R 7 is hydrogen or —NH 2 ;
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
4. The compound of claim 1 according to Formula IV:
wherein X is —OR 1 , —SR 1 , —NR 1 R 2 , or an N-linked amino acid or ester thereof;
where the N-linked amino acid is selected from alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, and histidinyl;
where the N-linked amino acid ester is is —NH-G(S c )—C(O)-Q 1 ; where Q 1 is unsubstituted alkoxyl; G is C 1 alkyl; S c is a side chain of a naturally occurring amino acid;
Base is
R 4 is hydrogen, hydroxyl, unsubstituted alkoxyl, —NH 2 , or alkyl substituted with an —NH 2 ;
R 5 is hydrogen, hydroxyl, —NH 2 , or unsubstituted alkoxyl;
R 6 is hydrogen, halogen, or unsubstituted alkyl; and
R 7 is hydrogen or —NH 2 ; or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
5. The compound of claim 1 according to Formula 1005:
wherein R 3 is alkoxyl or hydroxylalkyl;
R A is fluoro or hydroxyl;
Base is
R 4 is hydrogen, hydroxyl, unsubstituted alkoxyl, —NH 2 , or alkyl substituted with an —NH 2 ;
R 5 is hydrogen, hydroxyl, —NH 2 , or unsubstituted alkoxyl;
R 6 is hydrogen, halogen, or unsubstituted alkyl; and
R 7 is hydrogen or —NH 2 ;
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
6. A compound according to Formula 1002:
wherein:
R 11 is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, cycloalkyl, or unsubstituted aryl;
R 12 is a side chain of a naturally occurring amino acid selected from alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, and histidinyl; and
R 13 is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynylunsubstituted heterocycloalkyl, unsubstituted cycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;
R A is fluoro or hydroxyl;
Base is
R 4 is hydrogen, hydroxyl, unsubstituted alkoxyl, —NH 2 , or alkyl substituted with an —NH 2 ;
R 5 is hydrogen, hydroxyl, —NH 2 , or unsubstituted alkoxyl;
R 6 is hydrogen, halogen, or unsubstituted alkyl; and
R 7 is hydrogen or —NH 2 ;
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
7. A compound according to Formula 1003:
wherein:
R 10 is hydrogen, halogen, unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted aryl; and
R 11 is unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted aryl,;
R A is fluoro or hydroxyl;
Base is
R 4 is hydrogen, hydroxyl, unsubstituted alkoxyl, —NH 2 , or alkyl substituted with an —NH 2 ;
R 5 is hydrogen, hydroxyl, —NH 2 , or unsubstituted alkoxyl;
R 6 is hydrogen, halogen, or unsubstituted alkyl; and
R 7 is hydrogen or —NH 2 ;
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
8. A compound according to Formula 1004:
wherein:
R 10 is hydrogen, halogen, unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted aryl; and
R 11 is unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted aryl;
R A is fluoro or hydroxyl;
Base is
R 4 is hydrogen, hydroxyl, unsubstituted alkoxyl, —NH 2 , or alkyl substituted with an —NH 2 ;
R 5 is hydrogen, hydroxyl, —NH 2 , or unsubstituted alkoxyl;
R 6 is hydrogen, halogen, or unsubstituted alkyl; and
R 7 is hydrogen or —NH 2 ;
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
9. The compound of claim 1 according to Formula VI:
R A is fluoro or hydroxyl;
Base is
R 4 is hydrogen, hydroxyl, unsubstituted alkoxyl, —NH 2 , or alkyl substituted with an —NH 2 ;
R 5 is hydrogen, hydroxyl, —NH 2 , or unsubstituted alkoxyl;
R 6 is hydrogen, halogen, or unsubstituted alkyl; and
R 7 is hydrogen or —NH 2 ,
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
10. The compound of claim 1 according to any of Formulas VII-X:
where
R A is fluoro or hydroxyl;
R 6 is hydrogen, halogen, unsubstituted alkyl, or substituted alkyl; and
R 7 is hydrogen or —NH 2 ; or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
11. The compound of claim 1 according to any of Formulas XI-XIX:
R A is fluoro or hydroxyl;
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
12. The compound of claim 1 according to any of Formulas 101-105 and 201-205:
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
13. The compound of claim 1 wherein
Base is
R 4 is independently hydrogen, hydroxyl, unsubstituted alkoxyl, —NH 2 , or alkyl substituted with an —NH 2 ;
R 5 is independently hydrogen, hydroxyl, —NH 2 , or unsubstituted alkoxyl;
R 6 is independently hydrogen, halogen, or unsubstituted alkyl;
R 7 is independently hydrogen or —NH 2 ;
the N-linked amino acid is selected from alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, and histidinyl; and
the N-linked amino acid ester is —NH-G(S c )—C(O)-Q 1 ; where Q 1 is alkoxyl; G is C 1 alkyl;
S c is a side chain of a naturally occurring amino acid .
14. A pharmaceutical composition comprising the compound of claim 1 or 7 and a pharmaceutically acceptable excipient, carrier, or diluent.
15. A method for the treatment of a human host infected with a hepatitis C virus comprising administering to the host an effective amount of a compound or composition of any one of claim 1 or 7 .
16. The method of claim 15 comprising administering a second anti-viral agent in combination or alternation with the compound or the composition, wherein the second anti-viral agent is an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, or a combination thereof.