ASGPR-binding compounds for the degradation of extracellular proteins
Compounds and compositions that have an asialoglycoprotein receptor (ASGPR) binding ligand bound to an extracellular protein binding ligand for the selective degradation of the target extracellular protein in vivo to treat disorders mediated by the extracellular protein are described.
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 5 is selected from the group consisting of hydrogen, alkyl, alkenyl, and haloalkyl;
R 2 is-NR 6 -(5-membered heteroaryl), optionally substituted with 1 or 2 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, 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)—, —C(O)NR 6 —, —NR 6 C(O)—, —NR 6 —, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, —[O—CH 2 C(O)] n —, and —[C(O)—CH 2 —O] n —, each of which is optionally substituted with 1, 2, or 3 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, C 1 , 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 )—, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R 21 ;
Linker D is selected from:
R 32 is selected from the group consisting of alkyl, N′X—, —C—, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R 21 ;
X − is Br − or Cl − ; 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 selected from the group consisting of
each of which is optionally substituted with 1 [or 2]substituent 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 .
3 . The compound of claim 1 , wherein R 2 is
4 . The compound of claim 1 , wherein R 2 is
5 . The compound of claim 1 , wherein R 2 is
6 . The compound of claim 1 , wherein R 1 and R 5 are hydrogen.
7 . The compound of claim 1 Formula
or a pharmaceutically acceptable salt thereof.
8 . The compound of claim 1 , selected from the group consisting of
9 . The compound of claim 8 , wherein Linker B is selected from the group consisting of
10 . The compound of claim 1 of Formula
or a pharmaceutically acceptable salt thereof.
11 . The compound of claim 10 , wherein Linker A is bond.
12 . The compound of claim 10 , wherein Linker C is selected from the group consisting of
13 . The compound of claim 10 , wherein R 22 is selected from the group consisting of alkyl, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R 21.
14 . The compound of claim 1 of Formula
or a pharmaceutically acceptable salt thereof.
15 . The compound of claim 1 , wherein the targeted extracellular protein is immunoglobulin G.
16 . The compound of claim 15 , wherein the immunoglobulin G is an autoantibody.
17 . The compound of claim 16 , wherein the autoantibody binds citrullinated proteins.
18 . The compound of claim 1 , wherein the Extracellular Protein Targeting Ligand is a cyclic peptide.
19 . The compound of claim 1 , wherein the Extracellular Protein Targeting Ligand is Fc-III, FcBP-1, FcBP-2, or Fc-III-4c.
20 . 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 5 is selected from the group consisting of hydrogen, alkyl, alkenyl, and haloalkyl;
R 2 is-NR 6 -(5-membered heteroaryl), optionally substituted with 1 or 2 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, 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)—, —C(O)NR 6 —, —NR 9 C(O)—, —NR 6 —, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, —[O—CH 2 C(O)] n —, and —[C(O)—CH 2 —O] n —, each of which is optionally substituted with 1, 2, or 3 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, C 1 , 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:
R 22 is selected from the group consisting of alkyl, —C(O)N—, —NC(O)—, —N—, —C(R 21 )—, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R 21;
Linker D :
R 32 is selected from the group consisting of alkyl, N′X, —C—, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R 21 ;
X − is Br − or Cl − —; and
Extracellular Protein Targeting Ligand is a is a chemical moiety that binds to the targeted disease-modifying extracellular protein.
21 . The compound of claim 20 , wherein R 2 is selected from the group consisting of
each of which is optionally substituted with 1 substituent 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 .
22 . The compound of claim 20 , wherein R 2 is
23 . The compound of claim 20 , wherein R 2 is
24 . The compound of claim 20 , wherein R 2 is
25 . The compound of claim 20 , wherein R 1 and R 5 are hydrogen.
26 . The compound of claim 20 of Formula
or a pharmaceutically acceptable salt thereof.
27 . The compound of claim 26 , wherein R 22 is selected from the group consisting of alkyl, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R 21.
28 . The compound of claim 20 , wherein the targeted disease-modifying extracellular protein is immunoglobulin G.
29 . The compound of claim 28 , wherein the immunoglobulin G is an autoantibody.
30 . The compound of claim 29 , wherein the autoantibody binds citrullinated proteins.