Methods and compounds useful in conditions related to repeat expansion

1. A compound comprising a single-stranded oligonucleotide consisting of 13 to 30 linked nucleosides and having a nucleobase sequence complementary to a repeat region of an expanded repeat-containing target RNA, wherein the 5′-terminal nucleoside of the single-stranded oligonucleotide comprises a stabilized phosphate moiety and an internucleoside linking group linking the 5′-terminal nucleoside to the remainder of the oligonucleotide; wherein the oligonucleotide comprises a hybridizing region and 0-4 3′-terminal nucleosides, and wherein the hybridizing region has at least one mismatch relative to the repeat region of the expanded repeat-containing target RNA, wherein the 5′-terminal nucleoside of the single-stranded oligonucleotide has Formula I:

wherein:

T 1 is a phosphorus moiety;

T 2 is an internucleoside linking group linking the 5′-terminal nucleoside of Formula I to the remainder of the oligonucleotide;

A has a formula selected from among:

Q 1 and Q 2 are each independently selected from among: H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 2 -C 6 alkynyl, and N(R 3 )(R 4 );

Q 3 is selected from among: O, S, N(R 5 ), and C(R 6 )(R 7 );

each R 3 , R 4 , R 5 , R 6 and R 7 is independently selected from among: H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;

M 3 is selected from among: O, S, NR 14 , C(R 15 )(R 16 ), C(R 15 )(R 16 )C(R 17 )(R 18 ), C(R 15 )═C(R 17 ), OC(R 15 )(R 16 ), and OC(R 15 )(Bx 2 );

R 14 is selected from among: H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and substituted C 2 -C 6 alkynyl;

R 15 , R 16 , R 17 and R 18 are each independently selected from among: H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and substituted C 2 -C 6 alkynyl;

if Bx 2 is present, then Bx 2 is a nucleobase and Bx 1 is selected from among: H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and substituted C 2 -C 6 alkynyl;

if Bx 2 is not present, then Bx 1 is a nucleobase;

either each of J 4 , J 5 , J 6 and J 7 is independently selected from among: H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and substituted C 2 -C 6 alkynyl;

or J 4 forms a bridge with one of J 5 or J 7 wherein the bridge comprises from 1 to 3 linked biradical groups selected from O, S, NR 19 , C(R 20 )(R 21 ), C(R 20 )═C(R 21 ), C[═C(R 20 )(R 21 )] and C(═O) and the other two of J 5 , J 6 and J 7 are independently selected from among: H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and substituted C 2 -C 6 alkynyl;

each R 19 , R 20 and R 21 is independently selected from among: H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or substituted C 2 -C 6 alkynyl;

G is selected from among: H, OH, halogen, O—[C(R 8 )(R 9 )] n —[(C═O) m —X 1 ] j —Z, and a conjugate group;

each R 8 and R 9 is independently selected from among: H, halogen, C 1 -C 6 alkyl, and substituted C 1 -C 6 alkyl;

X 1 is O, S or N(E 1 );

Z is selected from among: H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 2 -C 6 alkynyl, and N(E 2 )(E 3 );

E 1 , E 2 and E 3 are each independently selected from among: H, C 1 -C 6 alkyl, and substituted C 1 -C 6 alkyl;

n is from 1 to 6;

m is 0 or 1;

j is 0 or 1;

provided that, if j is 1, then Z is other than halogen or N(E 2 )(E 3 );

each substituted group comprises one or more optionally protected substituent groups independently selected from among: a halogen, OJ 1 , N(J 1 )(J 2 ), ═NJ 1 , SJ 1 , N 3 , CN, OC(═X 2 )J 1 , OC(═X 2 )—N(J 1 )(J 2 ), and C(═X 2 )N(J 1 )(J 2 );

X 2 is O, S or NJ 3 ; and

each J 1 , J 2 and J 3 is independently selected from among: H and C 1 -C 6 alkyl.

2. The compound of claim 1 , wherein M 3 is O.

3. The compound of claim 2 , wherein each of J 4 , J 5 , J 6 and J 7 is H.

4. The compound of claim 3 , wherein A has the formula:

wherein:

Q 1 and Q 2 are each independently selected from among: H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and substituted C 1 -C 6 alkoxy.

5. The compound of claim 4 , wherein G is selected from among: a halogen, OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CH 3 , O(CH 2 ) 2 F, OCH 2 CHF 2 , OCH 2 CF 3 , OCH 2 —CH═CH 2 , O(CH 2 ) 2 —OCH 3 , O(CH 2 ) 2 —SCH 3 , O(CH 2 ) 2 —OCF 3 , O(CH 2 ) 3 —N(R 10 )(R 11 ), O(CH 2 ) 2 —ON(R 10 )(R 11 ), O(CH 2 ) 2 —O(CH 2 ) 2 —N(R 10 )(R 11 ), OCH 2 C(═O)—N(R 10 )(R 11 ), OCH 2 C(═O)—N(R 12 )—(CH 2 ) 2 —N(R 10 )(R 11 ), and O(CH 2 ) 2 —N(R 12 )—C(═NR 13 )[N(R 10 )(R 11 )]; wherein R 10 , R 11 , R 12 and R 13 are each, independently, H or C 1 -C 6 alkyl.

6. The compound of claim 5 , wherein G is selected from among: a halogen, OCH 3 , OCF 3 , OCH 2 CH 3 , OCH 2 CF 3 , OCH 2 —CH═CH 2 , O(CH 2 ) 2 —OCH 3 , O(CH 2 ) 2 —O(CH 2 ) 2 —N(CH 3 ) 2 , OCH 2 C(═O)—N(H)CH 3 , OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 , and OCH 2 —N(H)—C(═NH)NH 2 .

7. The compound of claim 6 , wherein G is selected from among: F, OCH 3 , and O(CH 2 ) 2 —OCH 3 .

8. The compound of claim 7 , wherein the oligonucleotide comprises 1-4 3′-terminal nucleosides.

9. The compound of claim 7 , wherein the hybridizing region has one mismatch relative to the repeat region of the expanded repeat-containing target RNA.

10. The compound of claim 7 , wherein the hybridizing region has two mismatches relative to the repeat region of the expanded repeat-containing target RNA.

11. The compound of claim 7 , wherein the hybridizing region has three mismatches relative to the repeat region of the expanded repeat-containing target RNA.

12. The compound of claim 7 , wherein the hybridizing region has four mismatches relative to the repeat region of the expanded repeat-containing target RNA.

13. The compound of claim 11 , having a mismatch at the eighth nucleobase from the 5′-end of the hybridizing region.

14. The compound of claim 11 , having a mismatch at the ninth nucleobase from the 5′-end of the hybridizing region.

15. The compound of claim 11 , having a mismatch at the tenth nucleobase from the 5′-end of the hybridizing region.

16. The compound of claim 7 , comprising at least one modified internucleoside linkage.

17. The compound of claim 7 , wherein each internucleoside linkage is selected from phosphorothioate and phosphodiester.

18. The compound of claim 7 , wherein each of the 6-10 3′-most internucleoside linkages is phosphorothioate linkage.