Compounds, compositions, and methods for the treatment of disease
Disclosed are compounds and compositions for the activation or induction of expression of a pattern recognition receptor (e.g., STING, RIG-I, MDA5), and methods of use thereof.
1. A compound of Formula (II):
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
Tm is a targeting moiety;
each of B 1 and B 2 is independently a purinyl nucleobase or pyrimidinyl 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 indpendently O or S;
each of Z 2 and Z 3 is independently absent, —C 1 -C 20 -alkylene, C 1 -C 20 -heteroalkylene, —OC(O)OC 1 -C 20 -alkylene, -cycloalkylene-, -heterocyclyl-, -aryl-, or -heteroaryl-, wherein each cycloalkylene-, -heterocyclyl-, -aryl- or -heteroaryl-is optionally substituted with one or more R 4 ;
Z 4 is self-immolative group-C 1 -C 20 -alkylene-Q 1 , heterocyclyl-C 1 -C 20 -alkylene-Q, —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 5 is a self-immolative group or absent;
T is a spacer group or absent;
L 1 is absent, —C 1 -C 6 - alkylene or —C 1 -C 6 - heteroalkylene;
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 absent, —C 1 -C 20 - alkylene, —O—, —N(R 5 )—, —S—, —S(O)—, —S(O) 2 -, —S(O)N(R 5 )-, —S(O) 2 N(R 5 )-, —N(R 5 )S(O)-, —N(R 5 )S(O) 2 -, —C(O)-, —C(O)O—, —OC(O)-, —C(O)N(R 5 )-, —N(R 5 )C(O)-;
L 4 is —C 1 -C 20 - alkylene, —C 1 -C 20 - heteroalkylene, —C 1 -C 20 - alkenylene, —C 1 -C 20 - alkynylene,
an oligopeptide,
wherein the oligopeptide is optionally substituted by one or more R 16 ;
L 5 is a linker connecting Z 4 and Z 5 , or is absent;
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 ;
R 3 is 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 ;
each R 4 is independently hydrogen, —C 1 -C 20 alkyl, —O—C 1 -C 20 alkyl, —C 1 -C 20 heteroalkyl, —OC 1 -C 20 -heteroalkylene, halo, —CN, —NO 2 or —OH;
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 16 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 Z 1 is O.
3. The compound of claim 1 , wherein B 1 is a purinyl nucleobase and B 2 is a pyrimidinyl nucleobase.
4. The compound of claim 1 , wherein B 1 is adenosinyl or guanosinyl and B 2 is cytosinyl, thyminyl, or uracilyl.
5. The compound of claim 1 , wherein each of R 1 and R 2 is halo.
6. The compound of claim 1 , wherein each of X 1 and X 2 is independently O.
7. The compound of claim 1 , wherein each of Y 1 and Y 2 is independently O or S.
8. The compound of claim 1 , wherein one of Y 1 or Y 2 is O and the other is S.
9. The compound of claim 1 , wherein each of Y 1 or Y 2 is independently S or O.
10. The compound of claim 1 , wherein each of L 1 and L 2 is independently C 1 -C 6 alkylene.
11. The compound of claim 1 , wherein L 1 is absent.
12. The compound of claim 1 , wherein R 3 is independently hydrogen, aryl, or heteroaryl, wherein aryl and heteroaryl is optionally substituted with 1-5 R 8 .
13. The compound of claim 1 , wherein R 3 is phenyl substituted with one R 8 .
14. The compound of claim 1 , wherein R 8 is —OC(O)-aryl, and the aryl is optionally substituted by 1-5 R 9 .
15. The compound of claim 14 , wherein R 9 is —O—C 1 -C 12 alkyl.
16. The compound of claim 1 , wherein Z 2 is -aryl-, —OC(O)OC 1 -C 20 -alkylene, or absent.
17. The compound of claim 1 , wherein L 3 is —O(O)C— or absent.
18. The compound of claim 1 , wherein Z 3 is -aryl-, —OC(O)OC 1 -C 20 -alkylene, —CH 2 CH 2 N(H)-, or absent.
19. The compound of claim 1 , wherein Z 3 is aryl substituted with —OC 1 -C 20 -heteroalkylene.
20. The compound of claim 1 , wherein L 4 is —C 1 -C 20 - alkylene or an oligopeptide.
21. The compound of claim 1 , wherein L 4 is an oligopeptide and 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.
22. The compound of claim 1 , wherein the oligopeptide is substituted with one R 16 ; and R 16 is C(O)NH 2 .
23. The compound of claim 1 , wherein L 4 is selected from the group
consisting of
24. The compound of claim 1 , wherein Z 4 is
and Q 1 is C(O).
25. The compound of claim 24 , wherein L 5 is absent; and Z 5 is absent.
26. The compound of claim 1 , wherein Tm is an antibody, a hormone, folic acid, a biotin, a small molecule, an oligopeptide, a sigma-2-ligand, or a sugar.
27. The compound of claim 26 , wherein Tm is an antibody; and the antibody is selected from 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, modified immunoglobulin molecules, an anti-CD22 antibody and an anti-CD79b antibody.
28. The compound of claim 26 , wherein Tm is an antibody; and the antibody is selected from 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.
29. The compound of claim 1 , wherein the compound is:
TABLE 1
Number
Compound
14
15
16
33
35
37
or a pharmaceutically acceptable salt thereof; wherein Tm is a targeting moiety.
30. A method of treating cancer 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 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.
32. 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.
33. A method of treating a microbial infection or a viral infection in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.