Oligonucleotide analogues having modified intersubunit linkages and/or terminal groups

1. An oligomer comprising a backbone, the backbone comprising a sequence of morpholino ring structures joined by intersubunit linkages, the intersubunit linkages joining a 3′-end of one morpholino ring structure to a 5′-end of an adjacent morpholino ring structure, wherein each morpholino ring structure is bound to a base-pairing moiety, such that the oligomer can bind in a sequence-specific manner to a target nucleic acid, wherein the intersubunit linkages have the following general structure (I):

or a salt, tautomer or stereoisomer thereof, and wherein each of the intersubunit linkages (I) are independently linkage (A) or linkage (B):

wherein for linkage (A):

W is, at each occurrence, independently S or O;

X is, at each occurrence, independently —N(CH 3 ) 2 , —NR 1 R 2 , —OR 3 or ;

Y is, at each occurrence, independently O or —NR 2 ,

R 1 is, at each occurrence, independently hydrogen or methyl;

R 2 is, at each occurrence, independently hydrogen or -LNR 4 R 5 R 7 ;

R 3 is, at each occurrence, independently hydrogen or C 1 -C 6 alkyl;

R 4 is, at each occurrence, independently hydrogen, methyl, —C(═NH)NH 2 , —Z-L-NHC(═NH)NH 2 or —[C(O)CHR′NH] m H, where Z is carbonyl (C(O)) or a direct bond, R′ is a side chain of a naturally occurring amino acid or a one- or two-carbon homolog thereof, and m is 1 to 6;

R 5 is, at each occurrence, independently hydrogen, methyl or an electron pair;

R 6 is, at each occurrence, independently hydrogen or methyl;

R 7 is, at each occurrence, independently hydrogen C 1 -C 6 alkyl or C 1 -C 6 alkoxyalkyl;

L is an optional linker up to 18 atoms in length comprising alkyl, alkoxy or alkylamino groups, or combinations thereof; and

wherein for linkage (B):

W is, at each occurrence, independently S or O;

X is, at each occurrence, independently —NR 8 R 9 or —OR 3 ; and

Y is, at each occurrence, independently O or —NR 10 ,

R 8 is, at each occurrence, independently hydrogen or C 2 -C 12 alkyl;

R 9 is, at each occurrence, independently hydrogen, C 1 -C 12 alkyl, C 1 -C 12 aralkyl or aryl;

R 10 is, at each occurrence, independently hydrogen, C 1 -C 12 alkyl or -LNR 4 R 5 R 7 ;

wherein R 8 and R 9 may join to form a 5-18 membered optionally substituted mono or bicyclic heterocycle or R 8 , R 9 or R 3 may join with R 10 to form a 5-7 membered heterocycle, and wherein when X is 4-piperazino, X has the following structure (III):

wherein:

R 11 is, at each occurrence, independently C 2 -C 12 alkyl, C 1 -C 12 aminoalkyl, C 1 -C 12 alkylcarbonyl, aryl, heteroaryl or heterocyclyl; and

R is, at each occurrence, independently an electron pair, hydrogen or C 1 -C 12 alkyl; and

R 12 is, at each occurrence, independently, hydrogen, C 1 -C 12 alkyl, C 1 -C 12 aminoalkyl, —NH 2 , —CONH 2 , —NR 13 R 14 R 15 , C 1 C 12 alkylcarbonyl, oxo, —CN, trifluoromethyl, amidyl, amidinyl, amidinylalkyl, amidinylalkylcarbonyl, guanidinyl, guanidinylalkyl, guanidinylalkylcarbonyl, cholate, deoxycholate, aryl, heteroaryl, heterocycle, —SR 13 or C 1 -C 12 alkoxy, wherein R 13 , R 14 and R 15 are, at each occurrence, independently C 1 -C 12 alkyl; and

wherein at least one of the intersubunit linkages is linkage (B) having the following structure (IV):

wherein Z represents a 5-18 member optionally substituted mono or bicycic heterocycle; or

wherein at least one of the intersubunit linkages is linkage (b) wherein X is —NR 8 R 9 and R 9 is C 1 -C 12 aralkyl or aryl.

2. The oligomer of claim 1 , wherein at least one of the morpholino ring structures has the following structure (i):

wherein Pi is, at each occurrence, independently a base-pairing moiety.

3. The oligomer of claim 1 , wherein at least one of the intersubunit linkages is linkage (A).

4. The oligomer of claim 1 , wherein X is —N(CH 3 ) 2 at each occurrence of linkage (A).

5. The oligomer of claim 1 , wherein W and Y are each O at each occurrence.

6. The oligomer of claim 1 , wherein at least one linkage (B) has the following structure (IV):

wherein Z represents a 5-18 membered mono or bicyclic heterocycle.

7. The oligomer of claim 6 , wherein Z has one of the following structures (III), (V), (VI), (VII) or (VIII):

8. The oligomer of claim 7 , wherein Z has structure (V).

9. The oligomer of claim 7 , wherein at least one R 12 has the following structure (IX):

wherein R 16 is, at each occurrence, independently hydrogen, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, —CN, aryl or heteroaryl.

10. The oligomer of claim 7 , wherein at least one R 12 is —NH 2 , —N(CH 3 ) 2 or —N + (CH 3 ) 3 .

11. The oligomer of claim 7 , wherein at least one R 12 is pyrrolidinyl, piperidinyl or mopholinyl.

12. The oligomer of claim 7 , wherein at least one R 12 is oxo, trifluoromethyl, guanidynyl or nitrile.

13. The oligomer of claim 7 , wherein R 11 is ethyl, isopropyl, piperidinyl, pyrimidinyl, cholate, deoxycholate or —C(═O)(CH 2 ) n CO 2 H, where n is 1 to 6.

14. The oligomer of claim 6 , wherein Z represents a crown ether.

15. The oligomer of claim 14 , wherein Z has one of the following structures (X) or (XI):

16. The oligomer of claim 1 , wherein at least one linkage (B) has the following structure (XII):

wherein Z′ represents a 5-7 membered heterocycle.

17. The oligomer of claim 16 , wherein the at least one linkage (B) has the following structure (XIII):

18. The oligomer of claim 1 , wherein R 8 is C 2 -C 12 alkyl and R 9 is C 1 -C 12 alkyl for at least one occurrence of linkage (B).

19. The oligomer of claim 1 , wherein R 9 is C 1 -C 12 aralkyl or aryl for at least one occurrence of linkage (B).

20. The oligomer of claim 19 , wherein R 9 has one of the following structures (XIV), (XV) or (XVI):

21. The oligomer of claim 1 , wherein at least one linkage (B) has one of the following structures:

22. The oligomer of claim 1 , wherein at least 5% of the intersubunit linkages are linkage (B).

23. The oligomer of claim 1 , wherein 10% to 50% of the intersubunit linkages are linkages (B).

24. The oligomer of claim 1 , wherein each linkage (B) has the same structure at each occurrence.

25. The oligomer of claim 1 , wherein each Y and each W are O.

26. The oligomer of claim 1 , wherein the oligomer has the following structure (XVII):

or a salt, tautomer or stereoisomer thereof, wherein:

R′ 17 is, at each occurrence, independently absent, hydrogen or C 1 -C 6 alkyl;

R 18 and R 19 are, at each occurrence, independently absent, hydrogen, a cell-penetrating peptide, a natural or non-natural amino acid, C 2 -C 30 alkylcarbonyl , —C(═O)OR 21 or R 20 ;

R 20 is, at each occurrence, independently guanidinyl, heterocyclyl, C 1 -C 30 alkyl, C 3 -C 8 cycloalkyl; C 6 -C 30 aryl, C 7 -C 30 aralkyl, C 3 -C 30 alkylcarbonyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkylalkylcarbonyl, C 7 -C 30 arylcarbonyl, C 7 -C 30 aralkylcarbonyl, C 2 - C 30 alkyloxycarbonyl, C 3 -C 8 cycloalkyloxycarbonyl, C 7 -C 30 aryloxycarbonyl, C 8 - C 30 aralkyloxycarbonyl, or —P(═O)(R 22 ) 2 ;

R 21 is C 30 alkyl comprising one or more oxygen or hydroxyl moieties or combinations thereof ;

each R 22 is independently C 6 -C 12 aryloxy

Pi is, at each occurrence, independently a base-pairing moiety;

L 1 is an optional linker up to 18 atoms in length comprising bonds selected from alkyl, hydroxyl, alkoxy, alkylamino, amide, ester, carbonyl, carbamate, phosphorodiamidate, phosphoroamidate, phosphorothioate and phosphodiester;

x is an integer of 0 or greater; and

provided that both of R 17 and R 8 are not absent.

27. The oligomer of claim 26 , wherein at least one of R 18 or R 19 is R 20 .

28. The oligomer of claim 26 , wherein R 20 is trityl, methoxytrityl, benzhydryl, p-chlorobenzhydryl, triphenylacetyl, triphenylpropyl, diphenylactyl, chlorodiphenylacetyl, hydroxydiphenylacetyl, triphenylphosphoryl, diphenylphosphoryl, geranyl, farnesyl, prenyl, lauroyl, trimethoxybenzoyl, triphenylpropionyl, trimethylglycine, 1-hydroxy-2,2-diphenyl acetyl, 9-fluorene-carboxyl, 5-carboxyfluorescein, —COCH 2 CH 2 SSPy, —COCH 2 SH, 4-carbazolylbenzoyl, 4-indazolylonebenzoyl, methylsuccinimidyl- cyclohexoyl, triethyleneglycoloyl, succinicacetyl, piperidin-4-yl, tritylpiperidin-4-yl, boc- piperidin-4-yl, hexyn-6-yl, piperazin-1-yl or guanidinyl.

29. The oligomer of claim 26 , wherein R ° is trityl or triphenylacetyl.

30. The oligomer of claim 26 , wherein R 19 is piperizinyl or

31. An oligomer comprising a backbone, the backbone comprising a sequence of morpholino ring structures joined by intersubunit linkages of type (A), (B), or combinations thereof, wherein each morpholino ring structure supports a base-pairing moiety, such that the oligomer compound can bind in a sequence-specific manner to a target nucleic acid, and wherein the oligomer comprises a 3′ terminus, a 5′ terminus and has the following structure (XVII):

or a salt, tautomer or stereoisomer thereof, and

wherein for linkage (A):

W is, at each occurrence, independently S or O;

X is, at each occurrence, independently —N(CH 3 ) 2 , —NR 1 R 2 , —OR 3 or ;

Y is, at each occurrence, independently O or —NR 2 ,

R 1 is, at each occurrence, independently hydrogen or methyl;

R 2 is, at each occurrence, independently hydrogen or -LNR 4 R 5 R 7 ;

R 3 is, at each occurrence, independently hydrogen or C 1 -C 6 alkyl;

R 4 is, at each occurrence, independently hydrogen, methyl, —C(═NH)NH 2 , —Z-L-NHC(═NH)NH 2 or —[C(O)CHR′NH] m H, where Z is carbonyl (C(O)) or a direct bond, R′ is a side chain of a naturally occurring amino acid or a one- or two-carbon homolog thereof, and m is 1 to 6;

R 5 is, at each occurrence, independently hydrogen, methyl or an electron pair;

R 6 is, at each occurrence, independently hydrogen or methyl;

R 7 is, at each occurrence, independently hydrogen C 1 -C 6 alkyl or C 1 -C 6 alkoxyalkyl;

L is an optional linker up to 18 atoms in length comprising alkyl, alkoxy or alkylamino groups, or combinations thereof; and

wherein for linkage (B):

W is, at each occurrence, independently S or O;

X is, at each occurrence, independently —NR 8 R 9 or —OR 3 ; and

Y is, at each occurrence, independently O or —NR   ,

R 8 is, at each occurrence, independently hydrogen or C 2 -C 12 alkyl;

R 9 is, at each occurrence, independently hydrogen, C 1 -C 12 alkyl, C 1 -C 12 aralkyl or aryl;

R 10 is, at each occurrence, independently hydrogen, C 1 -C 12 alkyl or -LNR 4 R 5 R 7 ;

wherein R 8 and R 9 may join to form a 5-18 membered mono or bicyclic heterocycle or R 8 , R 9 or R 3 may join with R 10 to form a 5-7 membered heterocycle, and wherein when X is 4-piparazino, X has the following structure (III):

wherein:

R 10 is, at each occurrence, independently C 2 -C 12 alkyl, C 1 -C 12 aminoalkyl, C 1 -C 12 alkylcarbonyl, aryl, heteroaryl or heterocyclyl; and

R 11 is, at each occurrence, independently an electron pair, hydrogen or C 1 -C 12 alkyl;

R 12 is, at each occurrence, independently, hydrogen, C 1 -C 12 alkyl, C 1 -C 12 aminoalkyl, —NH 2 , —CONH 2 , —NR 13 R 14 R 15 C 1 C 12 alkylcarbonyl, —CN, trifluoromethyl, amidyl, amidinyl, amidinylalkyl, amidinylalkylcarbonyl, guanidinyl, guanidinylalkyl, guanidinylalkylcarbonyl, cholate, deoxycholate, aryl, heteroaryl, heterocycle, —SR 13 or C 1 -C 12 alkoxy, wherein R 13 , R 14 and R 15 are, at each occurrence, independently C 1 -C 12 alkyl; and

R 17 is, at each occurrence, independently absent, hydrogen or C 1 -C 6 alkyl;

R 18 and R 19 are, at each occurrence, independently absent, hydrogen, a cell-penetrating peptide, a natural or non-natural amino acid, C 2 -C 30 alkylcarbonyl —C(═O)OR 21 or R 20 ;

R 20 is, at each occurrence, independently guanidinyl, heterocyclyl, C 1 -C 30 alkyl, C 3 -C 8 cycloalkyl; C 6 -C 30 aryl, C 7 -C 30 aralkyl, C 3 -C 30 alkylcarbonyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkylalkylcarbonyl, C 7 -C 30 arylcarbonyl, C 7 -C 30 aralkylcarbonyl, C 2 -C 30 alkyloxycarbonyl, C 3 -C 8 cycloalkyloxycarbonyl, C 7 -C 30 aryloxycarbonyl, C 3 -C 30 aralkyloxycarbonyl, or —P(═O)(R 22 ) 2 ;

R 21 is C 1 -C 30 alkyl comprising one or more oxygen or hydroxyl moieties or combinations thereof ;

each R 22 is independently C 6 -C 12 aryloxy;

Pi is, at ach occurrence independently a base-pairing moiety;

L 1 is an optional linker up to 18 atoms in length comprising bonds selected from alkyl, hydroxyl, alkoxy, alkylamino, amide, ester, disulfide, carbonyl, carbamate, phosphorodiamidate, phosphoroamidate, phosphorothioate, piperazine and phosphodiester;

x is an integer of 0 or greater; and

wherein at least one of R 18 or R 19 is R 20 and provided that both of R 17 and R 18 are not absent; and

wherein the oligomer comprises at least one linkage B having the following structure IV):

wherein Z represents a 5-18 membered optionally substituted mono or heterocycle or

wherein at east one of the intersubunit linkages is linkage (b) wherein X is —NR 8 R 9 and R 9 is C 1 -C 12 aralkyl or aryl.

32. A composition comprising the oligomer of claim 1 and a pharmaceutically acceptable vehicle.