Compounds, compositions, and methods for the treatment of disease

1. A compound of Formula (II):

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

Tm is a targeting moiety;

B 1 is a purinyl nucleobase and B 2 is a pyrimidinyl nucleobase, or B 1 is a pyrimidinyl nucleobase and B 2 is a purinyl nucleobase;

each of X 1 and X 2 is independently O or S;

each of Y 1 and Y 2 is independently O, S, or N(R 5 );

each of Z 1 is independently O or S;

Z 2 is —O—, —N(R 5 )—, —S—, —C(O)—, —C(O)N(R 5 )—, —OC(O)N(R 5 )—, —N(R 5 )C(O)O—, -aryl-, -heteroaryl-, —S(O)—, —S(O) 2 —, —S(O)N(R 5 )—, —S(O) 2 N(R 5 )— or —N(R 5 )S(O)—;

Z 3 is absent, hydrogen, heterocyclyl, heterocyclyl-C 1 -C 20 -alkylene-Q 1 , —OH, —N(R 5 ) 2 , SR 5 , —CHO, —C(O)N(R 5 ) 2 , —OC(O)N(R 5 ) 2 , —N(R 5 )C(O)OR 5 , aryl, heteroaryl, —S(O)R 5 , —S(O) 2 R 5 , —S(O)N(R 5 ) 2 , —S(O) 2 N(R 5 ) 2 , —N(R 5 )S(O)R 5 , —OSi(C 1 -C 4 alkyl) 3 , or —C(O)C 2 -C 6 alkenyl;

Z 4 is a self-immolative group or absent;

T is absent or a spacer group;

each L 1 and L 2 is absent, —C 1 -C 6 — alkylene or —C 1 -C 6 — heteroalkylene, wherein each alkylene and heteroalkyl is optionally substituted with one or more R 6 ;

L 3 is oligiopeptide-C(O)—, oligiopeptide-aryl-C 1 -C 6 -alkylene-, oligiopeptide-aryl-C 1 -C 6 -alklyene-C(O)—, oligiopeptide-aryl-C 1 -C 6 -heteroalkylene, oligiopeptide-C 1 -C 6 -alkylene-C(O)—, oligiopeptide-C 1 -C 6 -heteroalkylene-C(O)—, —C 1 -C 40 — alkylene, —C 1 -C 40 — heteroalkylene, —C 1 -C 40 — alkenylene, or —C 1 -C 40 — alkynylene, wherein the oligopeptide is optionally substituted by one or more R 14 ;

L 4 is absent or a linker connecting Z 3 and Z 4 ;

Q 1 is C(O), C(S), or CH 2 ;

each of R 1 and R 2 is independently hydrogen, halo, —CN, —C 1 -C 20 alkyl, or —OR 7 ;

each R 3 and R 4 is independently hydrogen, —C 1 -C 20 — alkyl, —C 1 -C 20 heteroalkyl, —OC(O)OC 1 -C 20 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 8 ;

R 5 is hydrogen or —C 1 -C 20 alkyl;

R 6 is halo, —CN, —C 1 -C 20 alkyl, —OR 7 , oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 9 ;

R 7 is hydrogen, —C 1 -C 20 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 9 ;

each R 8 is independently —C 1 -C 20 alkyl, —C 1 -C 20 heteroalkyl, —C(O)—C 1 -C 20 alkyl, —OC(O)—C 1 -C 20 alkyl, —C(O)O—C 1 -C 20 alkyl, —OC(O)O—C 1 -C 20 alkyl, —C(O)N(R 5 )—C 1 -C 20 alkyl, —N(R 5 )C(O)—C 1 -C 20 alkyl, —OC(O)N(R 5 )—C 1 -C 20 alkyl, —O-aryl, —O-heteroaryl, —C(O)-aryl, —C(O)-heteroaryl, —OC(O)-aryl, —C(O)O-aryl, —OC(O)-heteroaryl, —C(O)O-heteroaryl, —C(O)O-aryl, —C(O)O-heteroaryl, —C(O)N(R 5 )-aryl, —C(O)N(R 5 )-heteroaryl, —N(R 5 )C(O)-aryl, —N(R 5 ) 2 C(O)-aryl, or —N(R 5 )C(O)-heteroaryl, —S(O) 2 N(R 5 )-aryl, wherein each alkyl, heteroalkyl, aryl, and heteroaryl is optionally substituted by one or more R 9 ;

each R 9 is independently —C 1 -C 20 alkyl, —O—C 1 -C 20 alkyl, —C 1 -C 20 heteroalkyl, halo, —CN, —OH, oxo, aryl, heteroaryl, —O-aryl, or —O-heteroaryl; and

each R 14 is independently —C 1 -C 20 alkyl, C 1 -C 20 heteroalkyl, —OC(O)OC 1 -C 20 alkyl, C(O)N(R 4 ) 2 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

2. The compound of claim 1 , wherein each Z 1 is O.

3. The compound of claim 1 , wherein B 1 is adenosinyl or guanosinyl, and B 2 is cytosinyl, thyminyl, or uracilyl.

4. The compound of claim 1 , wherein each of R 1 and R 2 is independently hydrogen, halo, OR 7 , CN, or —C 1 -C 20 alkyl.

5. The compound of claim 1 , wherein each of X 1 and X 2 is independently O.

6. The compound of claim 1 , wherein each of Y 1 and Y 2 is independently O or S.

7. The compound of claim 1 , wherein one of Y 1 and Y 2 is O and the other of Y 1 and Y 2 is S.

8. The compound of claim 1 , wherein each of L 1 and L 2 is independently C 1 -C 6 alkylene.

9. The compound of claim 1 , wherein each of R 3 and R 4 is independently hydrogen, aryl, or heteroaryl, wherein aryl and heteroaryl is optionally substituted with 1-5 R 8 .

10. The compound of claim 1 , wherein R 3 is phenyl substituted with 1 R 8 , and R 4 is hydrogen.

11. The compound of claim 1 , wherein each of R 3 and R 4 is independently phenyl substituted with 1 R 8 .

12. The compound of claim 1 , wherein each of Y 1 and Y 2 is O and each of R 3 and R 4 is independently hydrogen.

13. The compound of claim 1 , wherein each of Y 1 and Y 2 is independently S and each of R 3 and R 4 is independently substituted with 1 R 8 .

14. The compound of claim 13 , wherein Y 1 is S and R 3 is substituted with 1 R 8 .

15. The compound of claim 1 , wherein R 8 is —OC(O)-aryl, and the aryl is optionally substituted by 1-5 R 9 .

16. The compound of claim 15 , wherein R 9 is —O—C 1 -C 12 alkyl.

17. The compound of claim 1 , wherein Z 2 is —N(R 5 )—; and R 5 is hydrogen.

18. The compound of claim 1 , wherein L 3 is C 1 -C 20 — alkylene, —C 1 -C 20 -heteroalkylene oligiopeptide-C(O)—, oligiopeptide-aryl-C 1 -C 6 -alkylene-, oligiopeptide-aryl-C 1 -C 6 -heteroalkylene, oligiopeptide-aryl-C 1 -C 6 -alklyene-C(O)—, oligiopeptide-C 1 -C 6 -alkylene-C(O)—, or oligiopeptide-C 1 -C 6 -heteroalkylene-C(O)—.

19. The compound of claim 18 , wherein the oligopeptide comprises 2 amino acid residues, 3 amino acid residues, 4 amino acid residues, 5 amino acid residues, 6 amino acid residues, 7 amino acid residues, 8 amino acid residues, 9 amino acid residues, or 10 amino acid residues.

20. The compound of claim 18 , wherein L 3 is

21. The compound of claim 1 , wherein Z 3 is

and Q 1 is C(O).

22. The compound of claim 21 , wherein L 4 is absent.

23. The compound of claim 22 , wherein T is absent.

24. The compound of claim 1 , wherein Tm is an antibody, a hormone, a hormone derivative, folic acid, a folic acid derivative, a biotin, a small molecule, an oligopeptide, a sigma-2-ligand, or a sugar.

25. The compound claim 24 , wherein the antibody is selected from the group consisting of intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments, single chain Fv (scFv) mutants, multispecific antibodies, bispecific antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins including an antigen determination portion of an antibody, immunoglobulin molecules including an antigen recognition site, an anti-CD22 antibody, and an anti-CD79b antibody.

26. The compound of claim 24 , wherein the antibody is selected from the group consisting of muromonab-CD3, abciximab, rituximab, daclizumab, palivizumab, infliximab, trastuzumab, etanercept, basiliximab, gemtuzumab ozogamicin, alemtuzumab, ibritumomab tiuxetan, adalimumab, alefacept, omalizumab, efalizumab, tositumomab-I 131 , cetuximab, bevacizumab, natalizumab, ranibizumab, panitumumab, eculizumab, rilonacept, certolizumab pegol, romiplostim, belimumab, anti-CD20, tocilizumab, atlizumab, mepolizumab, pertuzumab, tremelimumab, ticilimumab, inotuzumab ozogamicin, aflibercept, catumaxomab, pregovomab, motavizumab, efumgumab, Aurograb, raxibacumab, and veltuzumab.

27. The compound of claim 1 , wherein the compound is selected from the following table:

Number

Compound

1

2

3

4

5

6

9

12

15

18

20

22

or a pharmaceutically acceptable salt thereof; wherein Tm is a targeting moiety.

28. A method of alleviating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

29. A method of inducing the expression of a pattern recognition receptor (PRR) for immune-modulation in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

30. A method of inducing an immune response in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

31. A method of alleviating a microbial infection or a viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.