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US-12624044-B2 - SMARCA degraders and uses thereof

US12624044B2US 12624044 B2US12624044 B2US 12624044B2US-12624044-B2

Abstract

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same for the modulation of one or more SWI/SNF-related matrix associated actin dependent regulator of chromatin subfamily A (SMARCA) and/or polybromo-1 (PB-1) protein via ubiquitination and/or degradation by compounds. The compounds are bifunctional molecules that link a cereblon-binding moiety to a ligand that binds SMARCA and/or PB1 proteins.

Inventors

  • Nan Ji
  • Yi Zhang
  • Matthew M. Weiss
  • Paul R. Fleming

Assignees

  • KYMERA THERAPEUTICS, INC.

Dates

Publication Date
20260512
Application Date
20200610

Claims (16)

  1. 1 . A compound of any one of the following formulae formula: or a pharmaceutically acceptable salt thereof, wherein: L is, each R is independently hydrogen or C 1-6 aliphatic; and DIM is a compound of formula I-a: or a pharmaceutically acceptable salt thereof, wherein: X 1 is —C(O)—; X 2 is a carbon atom or silicon atom; X 3 is —CR 2 -; R 1 is hydrogen or C 1-4 aliphatic; each R 2 is independently hydrogen, R 6 , halogen, —CN, or —OR; Ring A is a bicyclic ring selected from Ring B is a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 3 is hydrogen; each R 4 is independently hydrogen or R 6 ; each R 6 is independently a group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond; and m is 0, 1, 2, 3 or 4.
  2. 2 . The compound of claim 1 , wherein DIM is:
  3. 3 . The compound of claim 1 , wherein said compound is selected from: or a pharmaceutically acceptable salt thereof.
  4. 4 . The compound of claim 1 , wherein X 2 is a carbon atom.
  5. 5 . The compound of claim 1 , wherein X 3 is —CH 2 —.
  6. 6 . The compound of claim 1 , wherein Ring A is
  7. 7 . The compound of claim 1 , wherein Ring B is a fused ring selected from a 6-membered aryl and a 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  8. 8 . The compound of claim 1 , wherein R 1 is hydrogen.
  9. 9 . The compound of claim 1 , wherein L is
  10. 10 . A pharmaceutical composition comprising a compound according to claim 3 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  11. 11 . The pharmaceutical composition according to claim 10 , further comprising an additional therapeutic agent.
  12. 12 . A method of degrading SMARCA2 or SMARCA4 protein in a patient or biological sample comprising administering to said patient, or contacting said biological sample with a compound of claim 1 , or a pharmaceutical composition thereof.
  13. 13 . A method of treating a SMARCA2-mediated or SMARCA4-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of claim 1 , or a pharmaceutical composition thereof.
  14. 14 . The method according to claim 13 , further comprising administration of an additional therapeutic agent.
  15. 15 . The method according to claim 13 , wherein the SMARCA2-mediated or SMARCA4-mediated-disorder, disease or condition is selected from a cancer, a neurodegenerative disease, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, a pathologic immune condition involving T cell activation, a cardiovascular disorder, and a CNS disorder.
  16. 16 . The method according to claim 15 , wherein the cancer is selected from lung cancer, breast cancer, pancreatic cancer, colorectal cancer, melanoma, leukemia, and malignant rhabdoid tumors (MRT).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a § 371 National Stage of PCT Application No. PCT/US2020/036916, filed Jun. 10, 2020, which claims the benefit under 35 U.S.C. § 119 (e) to U.S. Provisional Application No. 62/955,152 filed on Dec. 30, 2019, U.S. Provisional Application No. 62/949,796 filed on Dec. 18, 2019, U.S. Provisional Application No. 62/888,247 filed on Aug. 16, 2019, U.S. Provisional Application No. 62/875,374 filed on Jul. 17, 2019, and U.S. Provisional Application No. 62/859,305 filed on Jun. 10, 2019, each of which is hereby incorporated by reference in its entirety. TECHNICAL FIELD OF THE INVENTION The present disclosure relates to compounds and methods useful for the modulation of one or more SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A (“SMARCA”) and/or polybromo-1 (“PB1”) protein via ubiquitination and/or degradation by compounds according to the description provided herein. The disclosure also provides pharmaceutically acceptable compositions comprising compounds of the present description and methods of using said compositions in the treatment of various disorders. BACKGROUND OF THE INVENTION Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. There are over 600 E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3s. See e.g., Li et al. “Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling.” PLOS One 2008, (3)1487; Berndsen et al. “New insights into ubiquitin E3 ligase mechanism” Nat. Struct. Mol. Biol. 2014, 21:301; Deshaies et al. “RING domain E3 ubiquitin ligases” Ann. Rev. Biochem. 2009, 78:399; Spratt et al. “RBR E3 ubiquitin ligases: new structures, new insights, new questions” Biochem. 2014, 458:421; and Wang et al. “Roles of F-box proteins in cancer” Nat. Rev. Cancer. 2014, 14:233. UPP plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation. The pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman's syndrome, and Liddle syndrome), in immune surveillance/viral pathogenesis, and in the pathology of muscle wasting. Many diseases are associated with an abnormal UPP and negatively affect cell cycle and division, the cellular response to stress and to extracellular modulators, morphogenesis of neuronal networks, modulation of cell surface receptors, ion channels, the secretory pathway, DNA repair and biogenesis of organelles. Aberrations in the process have recently been implicated in the pathogenesis of several diseases, both inherited and acquired. These diseases fall into two major groups: (a) those that result from loss of function with the resultant stabilization of certain proteins, and (b) those that result from gain of function, i.e. abnormal or accelerated degradation of the protein target. The UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome-dependent degradation. Bifunctional compounds composed of a target protein-binding ligand and an E3 ubiquitin ligase ligand, induced proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression. Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins. See e.g., Crews, Chem. & Biol. 2010, 17(6):551; Schneekloth and Crews, ChemBioChem 2005, 6(1):40. An ongoing need exists in the art for effective treatments for disease, especially hyperplasias and cancers. However, non-specific effects, and the inability to target and modulate certain classes of proteins altogether, such as transcription factors, remain as obstacles to the development of effective anti-cancer agents. As such, small molecule therapeutic agents that leverage UPP mediated protein degradation to target cancer-associated proteins such a