1'-ALKYL MODIFIED RIBOSE DERIVATIVES AND METHODS OF USE
The present disclosure provides linker compounds of Formula (I) or (II): pharmaceutically acceptable salts thereof, and related scaffolds and conjugates. The present disclosure also relates to uses of the linker compounds, scaffolds, and conjugates, e.g., in delivering nucleic acid and/or treating or preventing diseases.
1 . A compound of Formula (I) or (II):
or a pharmaceutically acceptable salt thereof, wherein:
W is H, C 1 -C 6 alkyl optionally substituted with one or more halogen, or an amino substitution group;
X is H, halogen, or —OR X ;
R X is H, C 1 -C 6 alkyl, or —(C 1 -C 6 alkyl)-(C 6 -C 10 aryl), wherein the C 1 -C 6 alkyl or —(C 1 -C 6 alkyl)-(C 6 -C 10 aryl) is optionally substituted with one or more R Xa ;
each R Xa independently is halogen, C 1 -C 6 alkyl, or —O—(C 1 -C 6 alkyl), wherein the C 1 -C 6 alkyl or —O—(C 1 -C 6 alkyl) is optionally substituted with one or more halogen;
Y is H, C 1 -C 6 alkyl optionally substituted with one or more halogen, —P(R Y ) 2 , —P(OR Y )(N(R Y ) 2 ), —P(═O)(OR Y )R Y , —P(═S)(OR Y )R Y , —P(═O)(SR Y )R Y , —P(═S)(SR Y )R Y , —P(═O)(OR Y ) 2 , —P(═S)(OR Y ) 2 , —P(═O)(SR Y ) 2 , —P(═S)(SR Y ) 2 , or a hydroxy protecting group;
each R Y independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano;
Z is H, C 1 -C 6 alkyl optionally substituted with one or more halogen, —P(R Z ) 2 , —P(OR Z )(N(R Z ) 2 ), —P(═O)(OR Z )R Z , —P(═S)(OR Z )R Z , —P(═O)(SR Z )R Z , —P(═S)(SR Z )R Z , —P(═O)(OR Z ) 2 , —P(═S)(OR Z ) 2 , —P(═O)(SR Z ) 2 , —P(═S)(SR Z ) 2 , or a hydroxy protecting group;
each R Z independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano;
or Y and Z in Formula (I), together form —Si(R L ) 2 —O—Si(R L ) 2 —, wherein each R L independently is H or C 1 -C 6 alkyl;
each R a independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen; or two R a on two adjacent carbon atoms, together with the two adjacent carbon atoms, form a double bond;
each R b independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;
R 1 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;
R 2 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;
R 3 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;
R 4 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;
each R 5 independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen; and
n is an integer ranging from 0 to about 10.
2 .- 4 . (canceled)
5 . The compound of claim 1 , wherein W is H or C 1 -C 6 alkyl optionally substituted with one or more halogen.
6 . (canceled)
7 . The compound, scaffold of claim 1 , wherein W is an amino substitution group.
8 . The compound of claim 7 , wherein W is fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), optionally substituted acyl, trifluoroacetyl (TFA), benzyl, triphenylmethyl (Tr), 4,4′-dimethoxytrityl (DMTr), or toluenesulfonyl (Ts).
9 . The compound of claim 1 , wherein X is H or halogen.
10 . (canceled)
11 . The compound of claim 1 , wherein X is —OR X .
12 . The compound of claim 1 , wherein Y is H.
13 . The compound of claim 1 , wherein Y is C 1 -C 6 alkyl optionally substituted with one or more halogen.
14 . The compound of claim 1 , wherein Y is —P(R Y ) 2 , —P(OR Y )(N(R Y ) 2 ), —P(═O)(OR Y )R Y , —P(═S)(OR Y )R Y , —P(═O)(SR Y )R Y , —P(═S)(SR Y )R Y , —P(═O)(OR Y ) 2 , —P(═S)(OR Y ) 2 , —P(═O)(SR Y ) 2 , or —P(═S)(SR Y ) 2 .
15 . The compound of claim 1 , wherein Y is a hydroxy protecting group.
16 . The compound of claim 1 , wherein Z is H.
17 . The compound of claim 1 , wherein Z is C 1 -C 6 alkyl optionally substituted with one or more halogen.
18 . The compound of claim 1 , wherein Z is —P(R Z ) 2 , —P(OR Z )(N(R Z ) 2 ), —P(═O)(OR Z )R Z , —P(═S)(OR Z )R Z , —P(═O)(SR Z )R Z , —P(═S)(SR Z )R Z , —P(═O)(OR Z ) 2 , —P(═S)(OR Z ) 2 , —P(═O)(SR Z ) 2 , or —P(═S)(SR Z ) 2 .
19 . The compound of claim 1 , wherein Z is a hydroxy protecting group.
20 . The compound of claim 1 , wherein Y and Z in Formula (I) together form —Si(R L ) 2 —O—Si(R L ) 2 —.
21 . The compound of claim 1 , wherein the compound is of Formula (I′-1), (I′-2), (II′-1), or (II′-2):
or a pharmaceutically acceptable salt thereof.
22 . The compound of claim 1 , wherein the compound is of Formula (I-A), (II-A), (I-A′-1), (I-A′-2), (II-A′-1), or (II-A′-2):
or a pharmaceutically acceptable salt thereof.
23 . The compound of claim 1 , wherein the compound is of Formula (I-B), (II-B), (I-B′-1), (I-B′-2), (II-B′-1), or (II-B′-2):
or a pharmaceutically acceptable salt thereof.
24 . The compound of claim 1 , wherein the compound is selected from:
and pharmaceutically acceptable salts thereof.
25 .- 35 . (canceled)
36 . A pharmaceutical composition comprising the compound of claim 1 , and at least one pharmaceutically acceptable excipient or carrier.
37 .- 39 . (canceled)