Modulators of estrogen receptor proteolysis and associated methods of use

A halogen, enantiomer technology, applied in estrogen receptor proteolysis regulators and related fields of use, can solve problems such as non-specific effects hindering the development of effective therapeutic agents

Pending Publication Date: 2019-12-24
ARVINAS OPERATIONS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, non-specific effects and inability to target and regulate ER still hinder the development of effective therapeutics

Method used

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  • Modulators of estrogen receptor proteolysis and associated methods of use
  • Modulators of estrogen receptor proteolysis and associated methods of use
  • Modulators of estrogen receptor proteolysis and associated methods of use

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[1821] Preparation of intermediates:

[1822] Intermediate 1: (2S,4R)-1-[(2S)-2-Amino-3,3-dimethylbutyryl]-4-hydroxy-N-[(1S)-1-[4-(4 -Methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride

[1823]

[1824] Reagents and conditions: (a) (Boc) 2 O, NaHCO 3 , EtOAc / H 2 O; (b)(1)Pd(OAc) 2, KOAc, 90°C; (2) MeOH solution of 4NHCl; (c) (1) HATU, DIPEA, DMF; (2) LiOH, THF, H 2 O; (d) (1) intermediate compound 3, HATU, DIPEA, THF; (2) 4N HCl in MeOH

[1825] Step 1: Preparation of (S)-tert-butyl-1-(4-bromophenyl)-ethyl carbamate (2)

[1826] At 5°C, (S)-1-(4-bromophenyl)ethylamine (3.98g, 19.9mmol) and NaHCO 3 (1.24g, 14.8mmol) in H 2 To a mixture of O (10 mL) and ethyl acetate (10 mL) was added (Boc) 2 O (5.20 g, 23.8 mmol). The reaction lasted 2 hours. TLC showed the reaction was complete. The reaction mixture was filtered. The solid was collected and suspended in hexane (10 mL) and H 2 O (10 mL) for 0.5 h. The mixture was filtered, and the sol...

Embodiment

[1999] As described below, all compounds synthesized by 1 Characterization was performed by H-NMR and the purity was analyzed by LC / MS at wavelengths of 214 and 254 nM with UV detection. The purity of each compound in Tables 1-5 was over 90%. Molecular weights observed from LC / MS are given in Table 1, Table 2 and Table 3 as [M+H] + listed. The synthetic methods used to prepare the individual compounds are also listed in Tables 1-3.

[2000] All NMR experiments were recorded on a Bruker Mercury Plus 400NMR spectrometer equipped with a Bruker 400BBFO probe (at 400MHz for proton NMR) or on a Bruker Mercury Plus 300NMR spectrometer equipped with a Bruker 300BBFO probe (at 300MHz for proton NMR) . All deuterated solvents typically contain 0.03% to 0.05% v / v tetramethylsilane, which is used as a reference signal ( 1 H and 13 C are all set to δ0.00).

[2001] LC-MS analysis was performed on a SHIMADZU LC-MS machine consisting of a UFLC 20-AD system and a LCMS2020MS detector. ...

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Abstract

The present disclosure relates to bifunctional compounds, which find utility as modulators of estrogen receptor (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a cereblon, Von Hippel-Lindau ligase-binding moiety, Inhibitors of Apotosis Proteins, or mouse double-minute homolog 2 ligand, which binds to the respective E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation / inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 450,740, filed January 26, 2017, and U.S. Provisional Patent Application No. 62 / 587,378, filed November 16, 2017, both of which are incorporated in their entirety into this article. [0003] incorporated by reference [0004] U.S. Patent Application Serial No. 15 / 230,354, filed August 5, 2016; and U.S. Patent Application 15 / 206,497, filed July 11, 2016; and U.S. Patent Application 15 / 2016, filed July 13, 2016 209,648; and U.S. Patent Application Serial No. 15 / 730,728, filed October 11, 2017; and U.S. Patent Application Serial No. 14 / 686,640, filed April 14, 2015 and published as U.S. Patent Application Publication No. 2015 / 0291562 and U.S. Patent Application Serial No. 14 / 792,414, filed July 6, 2015, and published as U.S. Patent Application Publication No. 2016 / 0058872; and U.S. Patent Application Publication No. 2014 / 0356322, filed July 11, 2...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/12C07D409/14C07D471/04A61K31/381A61P35/00
CPCC07D401/14C07D471/04C07D409/12C07D403/06A61P35/00C07D405/14C07D413/14C07D417/12C07D417/14C07D403/14C07D409/14A61K31/381
Inventor Y·钱安德鲁·P·克鲁克雷格·M·克鲁斯H·董基思·R·霍恩伯格J·王
Owner ARVINAS OPERATIONS INC
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