Potent ASGPR-binding compounds for the degradation of immunoglobulins and other proteins
Extracellular protein degraders and compositions are provided that have a potent asialoglycoprotein receptor (ASGPR) Binding Ligand bound to an Extracellular Protein Targeting Ligand for the selective degradation of the Target Extracellular Protein, for example immunoglobulin in vivo to treat disorders mediated by the extracellular protein.
1. A compound of formula:
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 and R 5 are independently selected from hydrogen, C 0 -C 6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C 0 -C 6 alkyl-OR 6 , C 0 -C 6 alkyl-SR 6 , C 0 -C 6 alkyl-NR 6 R 7 , C 0 -C 6 alkyl-C(O)R 3 , C 0 -C 6 alkyl-S(O)R 3 , C 0 -C 6 alkyl-S(O) 2 R 3 , C 0 -C 6 alkyl-N(R 8 )—C(O)R 3 , C 0 -C 6 alkyl-O—C(O)R 3 , C 0 -C 6 alkylN 3 , and C 0 -C 6 alkyl-O—S(O) 2 R 3 ;
R 3 at each occurrence is independently selected from hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkynyl, aryl, heteroaryl, heterocycle, —OR 8 , and —NR 8 R 9 ;
R 6 and R 7 are independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR 8 , and C(O)R 3 ;
R 8 and R 9 are independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle;
R 10 is selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, and heterocycle;
R 65 , R 66 , and R 67 are independently selected from hydrogen, C 0 -C 6 alkyl-cyano, alkyl, haloalkyl, F, Cl, Br, I, C 0 -C 6 alkyl-OR 6 , C 0 -C 6 alkyl-NR 6 R 7 , C 0 -C 6 alkyl-C(O)R 3 , and C 0 -C 6 alkylN 3 ;
R 68 , R 69 , and R 70 are independently selected from hydrogen, alkyl, F, Cl, Br, I, C 0 -C 6 alkyl-OR 6 , C 0 -C 6 alkyl-NR 6 R 7 , C 0 -C 6 alkyl-C(O)R 3 , C 0 -C 6 alkyl-S(O)R 3 , C 0 -C 6 alkyl-N(R 8 )—C(O)R 3 , C 0 -C 6 alkylN 3 , heteroaryl, and aryl.
2. The compound of claim 1 , selected from
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 , of the formula
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 2 , selected from is selected from
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 3 , wherein R 66 and R 67 are hydrogen.
6. The compound of claim 1 , wherein R 65 is selected from hydrogen, CF 3 , cyano, F, Cl, Br, haloalkyl, heterocycle, haloalkoxy, C 0 -C 6 alkyl-OR 6 , and C 0 -C 6 alkyl-NR 6 R 7 .
7. The compound of claim 6 , wherein R 65 is hydrogen.
8. The compound of claim 6 , wherein R 66 is selected from hydrogen, CF 3 , cyano, F, Cl, Br, haloalkyl, heterocycle, haloalkoxy, C 0 -C 6 alkyl-OR 6 , and C 0 -C 6 alkyl-NR 6 R 7 .
9. The compound of claim 8 , wherein R 66 is hydrogen.
10. The compound of claim 8 , wherein R 67 is selected from hydrogen, CF 3 , cyano, F, Cl, Br, haloalkyl, heterocycle, haloalkoxy, C 0 -C 6 alkyl-OR 6 , and C 0 -C 6 alkyl-NR 6 R 7 .
11. The compound of claim 10 , wherein R 67 is hydrogen.
12. The compound of claim 1 , wherein R 68 is selected from hydrogen, CF 3 , cyano, F, Cl, Br, haloalkyl, heterocycle, haloalkoxy, C 0 -C 6 alkyl-OR 6 , and C 0 -C 6 alkyl-NR 6 R 7 .
13. The compound of claim 12 , wherein R 68 is hydrogen.
14. The compound of claim 12 , wherein R 69 is selected from hydrogen, CF 3 , cyano, F, Cl, Br, haloalkyl, heterocycle, haloalkoxy, C 0 -C 6 alkyl-OR 6 , and C 0 -C 6 alkyl-NR 6 R 7 .
15. The compound of claim 14 wherein R 69 is hydrogen.
16. The compound of claim 14 , wherein R 70 is selected from hydrogen, CF 3 , cyano, F, Cl, Br, haloalkyl, heterocycle, haloalkoxy, C 0 -C 6 alkyl-OR 6 , and C 0 -C 6 alkyl-NR 6 R 7 .
17. The compound of claim 16 , wherein R 70 is hydrogen.
18. The compound of claim 1 , wherein C 0 -C 6 alkyl is bond, C 1 alkyl, or C 2 alkyl.
19. The compound of claim 1 , wherein R 10 is hydrogen, alkyl, arylalkyl, heteroarylalkyl, heterocycle, C(O)R 3 , S(O)R 3 , or S(O) 2 R 3 .
20. The compound of claim 1 , wherein R 10 is hydrogen.
21. The compound of claim 1 , wherein R 1 is selected from hydrogen, C 0 -C 6 alkyl-cyano, alkyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C 0 -C 6 alkyl-OR 6 , C 0 -C 6 alkyl-NR 6 R 7 , C 0 -C 6 alkyl-C(O)R 3 , C 0 -C 6 alkyl-N(R 8 )—C(O)R 3 , and C 0 -C 6 alkyIN 3 .
22. The compound of claim 21 , wherein R 1 is selected from Cl, Br, haloalkoxy, C 0 -C 6 alkyl-OR 6 , C 0 -C 6 alkyl-NR 6 R 7 , C 0 -C 6 alkyl-C(O)R 3 , C 0 -C 6 alkyl-N(R 8 )—C(O)R 3 , and C 0 -C 6 alkylN 3 .
23. The compound of claim 22 , wherein R 6 is selected from hydrogen, arylalkyl, heteroarylalkyl, alkynyl, -alkyl-OR 8 , and C(O)R 3 .
24. The compound of claim 1 , of the formula
or a pharmaceutically acceptable salt thereof.
25. The compound of claim 24 , wherein R 10 is hydrogen.
26. The compound of claim 25 , wherein R 65 , R 66 , and R 67 are hydrogen.
27. A compound selected from:
or a pharmaceutically acceptable salt thereof.
28. A compound selected from:
or a pharmaceutically acceptable salt thereof.
29. A compound selected from
or a pharmaceutically acceptable salt thereof.