ASGPR-binding compounds for the degradation of extracellular proteins

1. A compound of formula:

or a pharmaceutically acceptable salt thereof;

wherein:

R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, and haloalkyl;

R 2 is selected from the group consisting of —NR 6 -heteroaryl and —NR 6 -aryl, each of which R 2 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of alkyl, alkenyl, haloalkyl, —OR 6 , F, Cl, Br, I, —NR 6 R 7 , heteroalkyl, cyano, nitro, and C(O)R 3 ;

R 3 at each occurrence is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, arylalkyl, alkenyl, aryl, heteroaryl, heterocycle, —OR 8 , and —NR 8 R 9 ;

R 6 and R 7 are independently selected at each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, alkenyl, aryl, haloalkyl, heteroaryl, heterocycle, and C(O)R 3 ;

R 8 and R 9 are independently selected at each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, alkenyl, aryl, heteroaryl, and heterocycle;

Linker A is bond;

Linker B is

R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 are independently at each occurrence selected from the group consisting of a bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—, —SO 2 —, —S(O)—, —C(S)—, —C(O)NR 6 —, —NR 6 C(O)—, —O—, —S—, —NR 6 —, —C(R 21 R 21 )—, —P(O)(R 3 )O—, —P(O)(R 3 )—, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, —CH 2 CH 2 —[O—(CH 2 ) 2 ] n —O—, —CH 2 CH 2 —[O—(CH 2 ) 2 ] n —NR 6 —, —CH 2 CH 2 —[O—(CH 2 ) 2 ] n —, —[—(CH 2 ) 2 —O—] n —, —[O—(CH 2 ) 2 ] n —, —[O—CH(CH 3 )C(O)] n —, —[C(O)—CH(CH 3 )—O] n —, —[O—CH 2 C(O)] n —, and —[C(O)—CH 2 —O] n —, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ;

n is independently selected at each instance from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

R 21 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, —NR 6 R 7 , —NR 8 SO 2 R 3 , —NR 8 S(O)R 3 , haloalkyl, aryl, heteroaryl, and heterocycle;

Linker C is selected from:

R 22 is selected from the group consisting of alkyl, —C(O)N—, —NC(O)—, —N—, —C(R 21 )—, —P(O)—, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ; and

Extracellular Protein Targeting Ligand is a means for binding the targeted extracellular protein that creates or exacerbates a disease.

2. The compound of claim 1 , wherein R 2 is —NR 6 -heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, haloalkyl, —OR 6 , F, Cl, Br, —NR 6 R 7 , heteroalkyl, cyano, nitro, and C(O)R 3 .

3. The compound of claim 2 , wherein R 6 is hydrogen.

4. The compound of claim 3 , wherein R 1 is hydrogen.

5. The compound of claim 1 , wherein R 2 is —NR 6 -heteroaryl substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, haloalkyl, —OR 6 , F, Cl, and —NR 6 R 7 .

6. The compound of claim 5 , wherein R 6 is hydrogen.

7. The compound of claim 6 , wherein heteroaryl which is substituted with 1 or 2 substituents is selected from the group consisting of

8. The compound of claim 7 , wherein the 1 or 2 substituents are independently selected from the group consisting of haloalkyl and halogen.

9. The compound of claim 8 , wherein halogen is fluorine or chloride.

10. The compound of claim 6 , wherein heteroaryl which is substituted with 1 or 2 substituents is selected from the group consisting of

11. The compound of claim 10 , wherein the 1 or 2 substituents are independently selected from the group consisting of haloalkyl and halogen.

12. The compound of claim 1 , wherein R 2 is —NR 6 -aryl.

13. The compound of claim 1 Formula:

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13 , wherein R 2 is —NR 6 -heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, haloalkyl, —OR 6 , F, Cl, Br, —NR 6 R 7 , heteroalkyl, cyano, nitro, and C(O)R 3 .

15. The compound of claim 14 , wherein Linker B is selected from the group consisting of

16. The compound of claim 14 , wherein Linker B is selected from the group consisting of

17. The compound of claim 1 of Formula:

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17 , wherein R 2 is —NR 6 -heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, haloalkyl, —OR 6 , F, Cl, Br, I, —NR 6 R 7 , heteroalkyl, cyano, nitro, and C(O)R 3 .

19. The compound of claim 18 , wherein Linker C is selected from:

20. The compound of claim 18 , wherein Linker C is selected from:

21. The compound of claim 1 , wherein the Extracellular Protein Targeting Ligand targets an immunoglobin.

22. The compound of claim 1 , wherein the Extracellular Protein Targeting Ligand targets IgA.

23. The compound of claim 1 , wherein the Extracellular Protein Targeting Ligand targets IgG.

24. The compound of claim 1 , wherein the Extracellular Protein Targeting Ligand targets IgE.

25. The compound of claim 1 , wherein the Extracellular Protein Targeting Ligand targets TNF-α.

26. The compound of claim 1 , wherein the Extracellular Protein Targeting Ligand targets IL-1b, IL-2, or IL-6.

27. The compound of claim 1 , wherein the Extracellular Protein Targeting Ligand targets IFN-7 or VEGF.

28. The compound of claim 1 , wherein the Extracellular Protein Targeting Ligand targets TGF-b1.

29. The compound of claim 1 , wherein the Extracellular Protein Targeting Ligand targets PCSK-9.

30. The compound of claim 8 , wherein haloalkyl is trifluoromethyl.