SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
Disclosed herein are nucleotide analogs, methods of synthesizing nucleotide analogs and methods of treating diseases and/or conditions such as a HCV infection with one or more nucleotide analogs.
1 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:
wherein:
B 1 is selected from the group consisting of an optionally substituted
an optionally substituted
and an optionally substituted
R 1 is selected from the group consisting of an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl, an optionally substituted C 2-6 alkynyl and an optionally substituted C 3-6 cycloalkyl;
each - - - - - - - - is absent or a single bond, provided that both are - - - - - - - each absent or both - - - - - - - - are each a single bond;
when both - - - - - - are each a single bond, then R 2 is halo, N 3 , —OR 7A or —N(R 7B R 7C ); R 4 is absent; R 3 is O; and R p is
wherein Z p is O or S and R p1 is selected from the group consisting of O − , OH, an —O-optionally substituted C 1-6 alkyl,
an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative;
when both - - - - - - are each absent, then R p is absent; R 2 is halo, N 3 , —OR 7A or —N(R 7B R 7C ); R 3 is —OH or —OC(═O)R 8 ; or R 2 and R 3 are each an oxygen atom which are linked together by a carbonyl group; and R 4 is hydrogen or
R 5A is selected from the group consisting of O − , OH, an optionally substituted N-linked amino acid, an optionally substituted N-linked amino acid ester derivative,
R 5B is selected from the group consisting of O − , OH, an —O-optionally substituted aryl, an —O-optionally substituted heteroaryl, an —O-optionally substituted heterocyclyl, an optionally substituted N-linked amino acid, an optionally substituted N-linked amino acid ester derivative,
R 6B and R 6C are independently selected from the group consisting of hydrogen, an unsubstituted C 1-6 alkyl, an unsubstituted C 3-6 alkenyl, an unsubstituted C 3-6 alkynyl and an unsubstituted C 3-6 cycloalkyl;
R 6D is NHR 6G ;
R 6E is hydrogen, halogen or NHR 6H ;
R 6G is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-6 alkenyl, an optionally substituted C 3-6 cycloalkyl, —C(═O)R A1 and —C(═O)OR A2 ;
R 6H is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-6 alkenyl, an optionally substituted C 3-6 cycloalkyl, —C(═O)R A3 and —C(═O)OR A4 ;
R 6I is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-6 alkenyl, an optionally substituted C 3-6 cycloalkyl, —C(═O)R A5 and —C(═O)OR A6 ;
X 1 is N or —CR 6J ,
R 6J is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl and an optionally substituted C 2-6 alkynyl;
R A1 , R A2 , R A3 , R A4 , R A5 and R A6 are independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 6-10 aryl, heteroaryl, heterocyclyl, aryl(C 1-6 alkyl), heteroaryl(C 1-6 alkyl) and heterocyclyl(C 1-6 alkyl);
R 7A is hydrogen or —C(═O)R 12 ;
R 7B and R 7C are independently hydrogen or an optionally substituted C 1-6 alkyl;
R 8 and R 12 are independently an optionally substituted C 1-6 alkyl or an optionally substituted C 3-6 cycloalkyl;
R 9 , R 10 and R 11 are independently absent or hydrogen;
R 8A , R 9A , R 11A , R 12A , R 9B , R 11B , R 12B , R p2 , R p3 , R p5 and R p6 are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl;
R 10A , R 10B , R 13A , R 13B , R p4 and R p7 are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl, an optionally substituted aryl, an optionally substituted —O—C 1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl;
R 14A , R 14B , R 15A , R 15B , R p8 and R p9 are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl;
n is 0 or 1;
p, q, and r are independently 1 or 2;
s, t and u are independently 3, 4 or 5;
Z 1 , Z 1A , Z 1B and Z p1 are independently O or S; and
provided that when R 4 is
and R 5A is O − or OH, then R 5B is O − , OH, or
an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.
2 . The compound of claim 1 , wherein R 2 is halo.
3 . The compound of claim 1 , wherein R 2 is —OR 7A .
4 . The compound of claim 3 , wherein R 7A is hydrogen.
5 . The compound of claim 1 , wherein R 2 is N 3 or NH 2 .
6 . The compound of claim 1 , wherein R 1 is an optionally substituted C 1-6 alkyl.
7 . The compound of claim 1 , wherein both - - - - - - are each absent.
8 . The compound of claim 7 , wherein R 3 is —OH.
9 . The compound of claim 7 , wherein R 4 is hydrogen.
10 . The compound of claim 7 , wherein R 4 is
11 . The compound of claim 10 , wherein R 5A is an optionally substituted N-linked amino acid or is an optionally substituted N-linked amino acid ester derivative; and R 5B is an optionally substituted N-linked amino acid or is an optionally substituted N-linked amino acid ester derivative.
12 . The compound of claim 10 , wherein:
R 5A has the structure
wherein R 13 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 14 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 15 is hydrogen or an optionally substituted C 1-4 -alkyl; or R 14 and R 15 is taken together to form an optionally substituted C 3-6 cycloalkyl; and
R 5B has the structure
wherein R 16 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 17 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 18 is hydrogen or an optionally substituted C 1-4 -alkyl; or R 17 and R 18 is taken together to form an optionally substituted C 3-6 cycloalkyl.
13 . The compound of claim 12 , wherein
are independently
14 . The compound of claim 10 , wherein R 5A is
and R 5B is
or wherein R 5A is
and R 5B is
or wherein R 5A is
and R 5B is
15 . The compound of claim 10 , wherein R 5A is an optionally substituted N-linked amino acid or is an optionally substituted N-linked amino acid ester derivative; and R 5B is an —O-optionally substituted aryl, an —O-optionally substituted heteroaryl or an —O-optionally substituted heterocyclyl.
16 . The compound of claim 10 , wherein R 5A is O − or OH; and R 5B is O − or OH; or wherein R 5A is O − or OH; R 5B is
and n is 0; or wherein R 5A is O − or OH; R 5B is
and n is 1.
17 . The compound of claim 10 , wherein Z 1 is O.
18 . The compound of claim 1 , wherein both - - - - - - are each a single bond.
19 . The compound of claim 18 , wherein R p1 is an —O-optionally substituted C 1-6 alkyl.
20 . (canceled)
21 . The compound of claim 1 , wherein B 1 is
or
22 . (canceled)
23 . The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt of the foregoing.
24 . 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.
25 . A method of ameliorating or treating a HCV infection comprising administering to a subject suffering from the HCV infection an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
26 . A method for inhibiting replication of a hepatitis C virus comprising contacting a cell infected with the hepatitis C virus with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
27 . A method for ameliorating or treating a HCV infection comprising contacting a cell infected with the hepatitis C virus with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
28 . (canceled)
29 . (canceled)