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US-12622972-B2 - ASGPR-binding compounds for the degradation of extracellular proteins

US12622972B2US 12622972 B2US12622972 B2US 12622972B2US-12622972-B2

Abstract

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.

Inventors

  • Mark George Saulnier
  • Jesse Jingyang Chen
  • Srinivasa Karra
  • Kevin Tyler Sprott
  • Jason Allan Wiles
  • Soumya Ray

Assignees

  • AVILAR THERAPEUTICS, INC.

Dates

Publication Date
20260512
Application Date
20250317

Claims (20)

  1. 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 , 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 10 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 ; 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, 3, or 4 substituents independently selected from R 21 ; X − is an anionic group; and Extracellular Protein Targeting Ligand is an IgE Targeting Ligand that binds IgE.
  2. 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 , cyano, nitro, and C(O) R 3 .
  3. 3 . The compound of claim 2 , wherein R 6 is hydrogen.
  4. 4 . The compound of claim 3 , wherein R 1 is hydrogen.
  5. 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 , halogen, and —NR 6 R 7 .
  6. 6 . The compound of claim 5 , wherein R 6 is hydrogen.
  7. 7 . The compound of claim 6 , wherein the heteroaryl which is substituted with 1 or 2 substituents is selected from the group consisting of
  8. 8 . The compound of claim 7 , wherein the 1 or 2 substituents are independently selected from the group consisting of haloalkyl and halogen.
  9. 9 . The compound of claim 8 , wherein haloalkyl is trifluoromethyl.
  10. 10 . The compound of claim 8 , wherein halogen is F.
  11. 11 . The compound of claim 6 , wherein heteroaryl which is substituted with 1 or 2 substituents is selected from the group consisting of
  12. 12 . The compound of claim 11 , wherein the 1 or 2 substituents are independently selected from the group consisting of haloalkyl and halogen.
  13. 13 . The compound of claim 1 , wherein R 2 is —NR 6 -aryl.
  14. 14 . The compound of claim 1 of Formula: or a pharmaceutically acceptable salt thereof.
  15. 15 . The compound of claim 14 , wherein R 2 is —NR 6 -(6-membered 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 , cyano, nitro, and C(O) R 3 .
  16. 16 . The compound of claim 15 , wherein Linker B is selected from the group consisting of
  17. 17 . The compound of claim 15 , wherein Linker B is selected from the group consisting of
  18. 18 . The compound of claim 1 of Formula: or a pharmaceutically acceptable salt thereof.
  19. 19 . The compound of claim 18 , wherein R 2 is —NR 6 -(6-membered 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 , cyano, nitro, and C(O) R 3 .
  20. 20 . The compound of claim 18 , wherein Linker C is selected from the group consisting of:

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 18/653,655, filed May 2, 2024, which is a continuation of U.S. patent application Ser. No. 18/220,708, filed Jul. 11, 2023, which is a continuation of U.S. patent application Ser. No. 17/877,538, filed Jul. 29, 2022, which is a continuation of International Patent Application No. PCT/US2021/015939, filed in the U.S. Receiving Office on Jan. 29, 2021, which claims the benefit of U.S. Provisional Patent Application No. 62/968,802, filed Jan. 31, 2020, and U.S. Provisional Patent Application No. 63/063,015, filed Aug. 7, 2020. The entirety of each of these applications is hereby incorporated by reference herein for all purposes. INCORPORATION BY REFERENCE The contents of the XML file named “19121-001WO1US2_SequenceListing_ST26.2” which was created on Sep. 19, 2023, and is 79.3 KB in size, are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION This invention provides 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. BACKGROUND OF THE INVENTION Historically, therapeutic strategies for the inhibition of proteins employed small molecule inhibitors which bound in an enzymatic pocket or at an allosteric position. Those proteins which were not enzymes were difficult to control, and some were considered “not druggable.” Intracellular protein degradation is a natural and highly regulated, essential process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins within the cell is achieved via the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of almost all intracellular processes. A number of companies and institutions have designed intracellular protein degrading molecules that take advantage of this natural process to degrade disease-mediating proteins intracellularly by linking a ligand to the protein to be degraded to a protein in the UPP. Examples are found in U.S. 2014/0356322 assigned to Yale University, GlaxoSmithKline, and Cambridge EntA122-1 erprise Limited University of Cambridge; Buckley et al. (J. Am. Chem. Soc. 2012, 134, 4465-4468) titled “Targeting the Von Hippel-Lindau E3 Ubiquitin Ligase Using Small Molecules to Disrupt the Vhl/Hif-1 alpha Interaction”; WO 2015/160845 assigned to Arvinas Inc. titled “Imide Based Modulators of Proteolysis and Associated Methods of Use”; Lu et al. (Chem. Biol. 2015, 22, 755-763) titled “Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target Brd4”; Bondeson et al. (Nat. Chem. Biol. 2015, 11, 611-617) titled “Catalytic in Vivo Protein Knockdown by Small-Molecule Protacs”; Gustafson et al. (Angewandte Chemie, International Edition in English 2015, 54, 9659-9662) titled “Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging”; Lai et al. (Angewandte Chemie, International Edition in English 2016, 55, 807-810) titled “Modular Protac Design for the Degradation of Oncogenic Bcr-Abl”; Toure et al. (Angew. Chem. Int. Ed. 2016, 55, 1966-1973) titled “Small-Molecule Protacs: New Approaches to Protein Degradation”; Winter et al. (Science 2015, 348, 1376-1381) titled “Drug Development. Phthalimide Conjugation as a Strategy for in Vivo Targeted Protein Degradation”; U.S. 2016/0058872 assigned to Arvinas, Inc. titled “Imide Based Modulators of Proteolysis and Associated Methods of Use” and U.S. 2016/0045607 assigned to Arvinas Inc. titled “Estrogen-related Receptor Alpha Based PROTAC Compounds and Associated Methods of Use”. The highjacking of the UPP intracellular process to degrade difficult or undruggable proteins, however, is not available to degrade extracellular proteins. Nonlimiting examples of extracellular proteins include immunoglobulins and cytokines, which can play a strong role in creating or exacerbating serious diseases. Immunoglobulins include IgA, IgG, IgD, IgE, and IgM. Cytokines are cell signaling peptides secreted into the bloodstream which cannot cross the lipid bilayer of cells to enter the cytoplasm, for example, interferons, interleukins, chemokines, lymphokines, MIP, and tumor necrosis factors. Cytokines are involved in autocrine, paracrine and endocrine signaling. They mediate immunity, inflammation and hematopoiesis. Cytokines are produced by immune cells (macrophages, B-cells, T-cells and mast cells), endothelial cells, fibroblasts and stromal cells. The asialoglycoprotein receptor (ASGPR) is a Ca2+-dependent lectin that is primarily expressed in parenchymal hepatocyte cells. The main role of ASGPRs is to help regulate serum glycoprotein levels by mediating endocytosis of desialylated glycoproteins (as depicted below). The receptor binds ligands with a terminal galactose or N-